Unrecognised actionability for breast cancer risk variants identified in a national-level review of Australian familial cancer centres

Unrecognised actionability for breast cancer risk variants identified in a national-level review of Australian familial cancer centres | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Unrecognised actionability for breast cancer risk variants identified in a national-level review of Australian familial cancer centres Amanda Spurdle, Cristina Fortuno, Elisa Cops, Aimee Davidson, and 23 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4352556/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Oct, 2024 Read the published version in European Journal of Human Genetics → Version 1 posted 9 You are reading this latest preprint version Abstract Breast cancer remains a significant global health challenge. In Australia, the adoption of publicly-funded multigene panel testing for eligible cancer patients has increased accessibility to personalised care, yet has also highlighted the increasing prevalence of variants of uncertain significance (VUS), complicating clinical decision-making. This project aimed to explore the spectrum and actionability of breast cancer VUS in Australian familial cancer centers (FCCs). Leveraging data from 11 FCCs participating in the Inherited Cancer Connect database, we retrieved VUS results from 1472 patients. Through ClinVar crosschecks and application of gene-specific ACMG/AMP guidelines, we showed the potential for reclassification of 4% of unique VUS as pathogenic or likely pathogenic, and 79% as benign or likely benign. Surveys conducted with FCCs and diagnostic laboratories described current practices and challenges in variant reclassifications, highlighting resource constraints preventing periodic VUS review and notifications from the laboratories to the FCCs. Our study suggests there are benefits to routine VUS review and reclassification, particularly in publicly-funded healthcare systems. Future research should focus on assessing the clinical impact and cost-effectiveness of implementing routine variant review practices, alongside efforts to enhance communication between FCCs and laboratories. Biological sciences/Genetics/Clinical genetics/Cancer genetics Health sciences/Health care/Diagnosis/Genetic testing Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Breast cancer is the most prevalent cancer diagnosed in women worldwide. The proportion of breast cancers in the general population attributed to BRCA1 and BRCA2 germline pathogenic variants is approximately 5–10% ( 1 , 2 ), but this proportion is much higher (up to 55%) in selected families referred to familial cancer clinics ( 3 ). Even though rarer than BRCA1 and BRCA2 , a short list of other highly penetrant genes are known to elevate breast cancer risk ( 4 ). In general, hereditary breast cancer is associated with poorer survival rates compared to breast cancer as a whole ( 5 , 6 ). Genetic testing is valuable as it provides patients and their close relatives with knowledge about their hereditary cancer risk, and guides personalised strategies for cancer prevention and treatment for both pathogenic variant carriers and those with “normal” results (no germline pathogenic variant identified). Multigene panel testing has been adopted as a cost-effective strategy to simultaneously sequence multiple genes, however these panels reveal variants of uncertain significance (VUS) more frequently than single gene testing approaches. Identification of VUS presents an important challenge to the clinical utility of precision genomic medicine ( 7 ). These variants not only limit effective clinical management but are also a source of anxiety and confusion for some clinicians, and for patients and their family members ( 8 ). Presently, there are no definitive recommendations regarding the reporting of VUS, and attitudes on their disclosure vary among clinical and laboratory genetic counsellors ( 9 ). Testing of breast cancer predisposition genes increased significantly in Australia following the introduction of national government funding of multigene panel testing in 2017. This is expected to have led to a corresponding increase in the number of breast cancer gene VUS identified. One Australian clinical genetic testing program employing multigene testing for breast cancer (covering BRCA1, BRCA2, PALB2, TP53 and ATM ), reported a VUS detection rate of 8.7% ( 10 ), however the proportion of breast cancer gene variants reported as VUS in ClinVar, as at 21 April 2024, is notably higher. For the subset of genes whose testing is publicly funded in Australia ( BRCA1, BRCA2, CDH1, PALB2, PTEN, TP53 ), the VUS rate in ClinVar ranges from 16% to ( BRCA1 ) to 47% ( CDH1 ) (Fig. 1 ). Furthermore, when variants with conflicting classifications are taken into account, these two categories collectively constitute at least a third of all variants in each gene. VUS reclassification has potential to alter clinical management in hereditary cancer patients ( 11 ), however little is known about the prevalence and potential for VUS reclassifications among breast cancer patients. The rate of VUS reclassification from purposeful variant reclassification efforts using American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines was 61% for a study of 92 patients with any VUS received through clinical testing ( 12 ), with ranges of up to 81.3% for BRCA1/2 -focused studies ( 13 – 17 ). It is therefore reasonable to think that reclassification of VUS in breast cancer risk genes has potential to improve patient clinical management. The aim of this project was to identify the scope of the problem of breast cancer VUS in Australian familial cancer centres (FCCs), and to understand reclassification processes and interaction between FCCs and diagnostic laboratories, in order to consider future strategies for increased actionability and improved clinical management of breast cancer patients. Materials and Methods An overview of the study process is shown in Fig. 2 . Data acquisition We engaged with 11 Australian FCCs participating in the Inherited Cancer Connect (ICCon) partnership (Forrest, 2018) to retrieve the breast cancer gene variants listed as VUS in their internal databases in the following genes eligible for publicly-funded testing in Australia: BRCA1, BRCA2, CDH1, PALB2, PTEN , and TP53 . The participating FCCs were: ACT Genetic Service, Austin Health, the Adult Genetics Unit (a state-wide service for South Australia), Genetic Health Queensland, Genetic Health WA, Liverpool Cancer Genetics, Peter MacCallum Cancer Centre, Princes of Wales Hospital, Royal Melbourne Hospital, Royal North Shore, and St. George Hospital. Data retrieved corresponded to VUS results for patients undergoing multigene panel testing due to hereditary cancer risk identified post-2017 and up to 2022. For the six selected genes, we received VUS results from 1,516 patients. We first checked for nomenclature errors using the Mutalyzer tool ( 18 ). Entries for 44 patients were unresolvable and were excluded. The nomenclature for the remaining entries was standardized as per HGVS recommendations. ClinVar crosscheck and groupings To ascertain the extent to which variants labelled as "VUS" in FCC internal databases may have resulted from outdated or inadequately reassessed historical reports, we initially examined their classifications in ClinVar (as at 1 September 2022). These variants were categorised into four distinct groups, as follows: Variants with Expert Panel submissions as Likely pathogenic and Pathogenic (hereafter referred to as P/LP) or Likely benign and Benign (hereafter referred to as B/LB) Variants with multiple non-conflicting submissions as P/LP or B/LB Variants with a single submission as P/LP or B/LB Variants not belonging to any of these groups (i.e. variants with conflicting submissions, variants classified as Uncertain, and variants not previously submitted to ClinVar), hereafter referred to as “Other” Gene-specific ACMG/AMP guidelines application We applied gene-specific ACMG/AMP criteria to variants in the “Other” ClinVar group, using the following criteria specifications versions: BRCA1 v1.1.0, BRCA2 v1.1.0, CDH1 v3.1.0, PALB2 v1.1.0, PTEN v3.0.0, and TP53 v1.4.0. Details for specifications are available in the ClinGen Criteria Specification Registry ( https://cspec.genome.network/cspec/ui/svi/ ). For the population-based codes (BA1, BS1, PM2), we used the gnomAD v4.0 database ( 19 ), except for BRCA1 and BRCA2 for which we performed this step prior to v4.0 release, and whose latest guidelines specify the use of gnomAD v2.1 and gnomAD v3.1 (non-cancer datasets). For all genes, the cutoffs used for SpliceAI splicing predictions were ≥ 0.2 (predicted impact) and ≤ 0.1 (no predicted impact), as recommended by the ClinGen Sequence Variant Interpretation Splicing Subgroup ( 20 ). All other codes were assigned following the respective gene specifications. The proposed class following review was assigned based on a Bayesian point systems ( 21 ), which included reclassifying as LB variants with a total of -1 points where the only pathogenic code applied is PM2_Supporting, and there are at least two benign codes applied. Surveys to FCCs and diagnostic laboratories To enhance comprehension of the VUS review process and the dynamics between FCCs and diagnostic laboratories in Australia, as well as to identify unmet clinical needs, we developed two surveys: An eight-question survey was sent to each FCC representative, totalling nine representatives from 11 FCCs. The survey aimed to gain insights into how FCCs become aware of VUS reclassifications, actions taken post-notification of VUS upgrades/downgrades, and reasons for failing to update their internal clinical database. A 13-question survey was sent to each laboratory designated as being used by the FCCs, totalling six representatives from six laboratories. This survey sought to understand the reasons prompting VUS review, the frequency and constraints of VUS review, how laboratories learn of new Expert Panel classifications and subsequent actions, notifications of reclassifications to FCCs, and perspectives on the significance of regular VUS review. Both of these surveys comprised multiple-choice questions, all of which had an option to provide additional comments when considered relevant, as well as separate open-ended questions. Results Variant spectrum per gene and ClinVar group Data was available from 1472 patient records for breast cancer gene variants from all 11 participating FCCs, corresponding to 944 unique variants recorded as “VUS” across the FCC internal databases. Of these, the number of VUS per gene was as follows: 522 in BRCA2 , 265 in BRCA1 , 104 in PALB2 , 37 in TP53 , 11 in PTEN , and five in CDH1 . An overview of the results from the ClinVar crosscheck is shown in Fig. 3 . At the time (1 September 2022), approximately 20% of the unique VUS had Expert Panel submissions as P/LP ( 11 ) and B/LB (175), while 5% had multiple non-conflicting submissions in the same directions (9 P/LP and 36 B/LB). Additionally, two VUS had a single submission as P/LP, while 13 had a single submission as B/LB. For each gene, most of the VUS were in the “Other” group. Results from the ClinVar crosscheck were returned to FCC representatives prior to the surveys for consideration of possible reclassification review, in particular variants with ClinVar assertions apart from VUS from Expert Panels or with multiple non-conflicting submissions. Gene-specific ACMG/AMP application We applied gene-specific ACMG/AMP guidelines to all the VUS in the “Other” ClinVar group (total 698 variants). The number of our resulting proposed reclassifications per gene is shown in Fig. 4 . There was no suggested reclassification for three CDH1 variants. Application of the specifications for the remaining genes overall reclassified 3% of all variants as P/LP (19 out of the 698 “Other” VUS), and 77% variants as B/LB (534). These variants, codes applied, and our suggested classification are detailed in Supplementary Table 1. As an update, we added updated ClinVar classification details (as at 27 January 2024). Results from FCC survey We received survey results from representatives of all 11 participating FCCs, with some clinicians answering on behalf of multiple centres. A simplified summary of key survey results is shown in Table 1 . Table 1 Summary of relevant responses from the FCC survey by nine representatives* • How FCCs report to become aware of VUS reclassifications - Laboratory/s routinely inform them of VUS upgrades (VUS to P/LP) for reports of existing patients (4/9) - Laboratory/s routinely inform them of VUS downgrades (VUS to B/LB) for reports of existing patients (3/9) - There is a diagnostic report for a new patient with the same variant (3/9) - Regular review of variants in internal clinical database (2/9) - Other: review with the laboratory when patients contacts for more information ( 3 ), referral of a relative ( 3 ), local and/or national MDT meetings ( 1 ) • Clinical actions taken by FCCs after VUS reclassifications - VUS upgrades: Request re-issue of a report for patients with an alternative pre-existing classification (9/9) - VUS downgrades: Request re-issue of a report for patients with an alternative pre-existing classification (6/9) • Reasons for not updating internal clinical database - Not being aware of a VUS reclassification (8/9) - Lack of resources (3/9) - Not clinically necessary (1/9) *Responses without the denominator noted (“/”) refer to open-ended questions Abbreviations: B/LB = Benign/Likely benign; FCC = Familial cancer centre; MDT = Multidisciplinary team; P/LP = Pathogenic/Likely pathogenic; VUS = Variant of uncertain significance Regarding how FCCs become aware of VUS reclassifications, four of the nine FCC representatives reported that their laboratory provider routinely notifies them of VUS upgrades, while this number decreased to three for downgrades. Other methods selected were receiving a diagnostic report for a new patient with the same variant (3/9) and conducting regular reviews of variants within their internal clinical database (2/9). Additionally, some FCC representatives provided free-text responses citing additional reasons such as patients reaching out for more information ( 3 ), referral of a relative ( 3 ), and involvement in local and/or national multidisciplinary team (MDT) meetings ( 1 ). As per actions taken upon VUS reclassifications, it was found that all participating FCCs requested the re-issue of reports for patients in cases of VUS upgrades, whereas only six out of nine FCC representatives did so for variant downgrades. Lastly, the majority of FCC representatives reported that the primary reason for the lack of updates in their internal clinical databases was their unawareness of VUS reclassifications (8/9), with a lack of resources also cited as a contributing factor by a third of the representatives (3/9), and not considered clinically necessary by one representative (1/9). Results from laboratory survey We received survey results from representatives of all six participating laboratories. A summary of the responses regarding activities prompting review of previously identified VUS is presented in Table 2 , with a scale provided from 1 (least often) to 5 (most often) for the activities considered relevant by the laboratories. Table 2 Summary of activities most commonly prompting VUS review as reported by six laboratory representatives Activity Scale from 1 (least often) to 5 (most often) Average* Lab 1 Lab 2 Lab 3 Lab 4 Lab 5 Lab 6 FCC/clinician contacts the lab for more/updated information 5 1 2 5 5 5 3.8 The laboratory identifies new evidence (clinical, functional etc.) for a specific variant 2 5 4 3 2 2 3.0 FCC/clinician provides information to justify variant re-review 4 2 1 1 2 4 2.3 New classification guidelines/recommendations become available 3 3 - 2 1 3 2.0 Regular VUS review as part of the laboratory SOP 5 5 - - - 1 1.8 A new evidence type/algorithm is included in the lab SOP 1 3 - 2 1 2 1.5 New ClinVar Expert Panel submissions are available 2 2 - 1 1 3 1.5 New ClinVar laboratory or research submissions are available 1 - - 1 1 2 0.8 The laboratory generates or accesses external research findings 1 - - - 1 2 0.7 *The scale of activities not considered relevant, marked with a “-”, was counted as 0 for average calculations Abbreviations: FCC = Familial cancer centre; VUS = Variant of uncertain significance The activity most commonly cited as prompting review was FCCs contacting laboratories for additional information (average rating of 3.83), followed by laboratories identifying new evidence (average rating of 3). Conversely, activities least likely to prompt VUS review included laboratories generating or accessing external research findings (average rating of 0.7), followed by the availability of new ClinVar submissions (average rating of 0.8). A simplified summary of other key survey results from the six laboratory representatives is shown in Table 3 . Only two out of six laboratories reported conducting regular reviews of VUS, one annually, the other at least biannually. Lack of resources was cited by all laboratories as a primary reason for not regularly conducting this activity. Additional reasons noted by half of the laboratories were an inability to track previous results for variants not included in reports, and the activity not deemed clinically relevant unless prompted by FCCs for additional information. Table 3 Summary of other relevant responses from the diagnostic laboratory survey by six representatives* • Frequency of VUS review - Every 1 or 2 years (2/6) - No regular review (4/6) • Reasons limiting regular VUS review - Resources (6/6) - Inability to track previous results for variants not included in reports (3/6) - Not considered clinically relevant unless FCCs contact for more information (3/6) • How laboratories report to become aware of new Expert Panel reclassifications - By being members of ClinGen ( 2 ) - No single established process ( 4 ) • Actions taken after laboratories become aware of a new Expert Panel reclassification - Review and/or discuss the information provided ( 3 ) - Reclassify the variant ( 1 ) - Inform the relevant FCC ( 1 ) • Routine notification of reclassifications to the FCCs - Yes for variant upgrades (6/6) - Yes for variant downgrades (5/6) • Existence of a documented process in place by which VUS reclassifications are notified to the FCCs - Yes (5/6) • Prioritisation of VUS regular review if there was more funding - Yes (5/6) *Responses without the denominator noted (“/”) refer to open-ended questions Abbreviations: FCC = Familial cancer centre; VUS = Variant of uncertain significance Regarding awareness of new Expert Panel reclassifications in an open-ended survey question, two out of the six laboratories indicated that they had easier access to these updates by virtue of being VCEP members, while the remaining laboratories lacked a standardised process. Another open-ended survey question revealed the following actions taken following new Expert Panel reclassifications, including: review and/or discussion of provided information for potential reclassification ( 3 ); reclassification of relevant variants ( 1 ); and informing the relevant FCC to request a reclassification from the lab ( 1 ). With regards to notifications to FCCs, all laboratories reported notifying FCCs of VUS upgrades, compared to five out of six for downgrades. One of the laboratories reporting notifications of both options added a note to clarify that these were expected actions, since they would only review VUS following a previous FCC enquiry. The majority of laboratories reported having a documented process in place for notifying FCCs of VUS reclassifications (5/6). Lastly, all laboratories except one indicated that VUS regular review would be prioritised if additional funding were available (5/6). Discussion We have performed a nation-wide audit of VUS recorded in the clinical databases of Australian familial cancer services to determine the scale of unrecognised actionability, and to map the current and required processes to achieve effective variant review. Our ultimate aim is to inform future improvements in Australian practices concerning variant classification, reducing variant uncertainty and improving patient clinical management. With a straightforward crosscheck of the 944 clinically detected VUS retrieved from FCCs against ClinVar, we found that a notable number of the historical reports recorded in FCC internal clinical databases had not undergone updates and/or reassessment with existing new evidence. Approximately 20% of the so-called VUS had an Expert Panel submission as P/LP or B/LB, with an additional 5% exhibiting multiple non-conflicting submissions in the same categories, information that was returned to the FCCs. Most of these ClinVar submissions were in the benign direction, however there are many reasons to consider variant downgrades as clinically important, including the opportunity to avoid unnecessary clinical risk management interventions or relief from any continuing anxiety, although it can also be an indication to continue searching for alternative genetic explanations. According to the results from the survey of FCCs, the majority of reclassifications in either direction, specifically 100% of VUS upgrades and 67% of downgrades, would be communicated to patients. This attitude aligns with findings from a US-based survey study where both oncologists and genetic counsellors concurred that all reclassified variants, even when they do not represent a change in clinical management, should be disclosed to patients ( 22 ). Of the greatest concern though were the 11 variants with Expert Panel submissions as P/LP, alongside nine variants with multiple non-conflicting P/LP submissions (collectively corresponding to 26 patients), which have a more clear-cut implication for the management of the patients and their family members. For the large group of remaining variants that are VUS, conflicting in ClinVar or absent from the database altogether, we found that application of gene-specific guidelines developed by ClinGen Expert Panels resulted in a 79% reduction in the VUS rate, even when relying solely on publicly available information. Of the 698 variants in the “Other” ClinVar group (as at 1 September 2022), 3% (19 variants) could be reclassified as P/LP and 77% (534) as B/LB by the application of gene-specific guidelines. When added to the variants with Expert Panel or multiple non-conflicting submissions, our analysis suggests that a total of 4% of the initially provided 944 unique VUS (39 variants), could potentially be reclassified as P/LP, while more than three quarters of the VUS (745 out of 944, 79%) could be reclassified as B/LB utilising this approach. To better understand the factors contributing to these findings, and to describe the barriers to FCCs and laboratory identifying and implementing reclassifications, we surveyed both groups. Representatives from a large majority of FCCs (89%) indicated that they do not routinely update their internal variant database as they are generally not aware of any potential reclassifications. On the other hand, in the laboratory survey results, laboratories indicated that they notify the FCCs of variant reclassifications in nearly all instances, with the primary reason prompting VUS review being an FCC request to the laboratory for additional or updated information. This highlights a major flaw in the current VUS review process: FCCs heavily rely on laboratories to keep them updated of variant reclassifications, as they do not have the clinical capacity and/or expertise to do their own reviews, but laboratories rarely initiate VUS review without a clinical prompt. The results suggest that only a relatively low proportion of VUS found in patients will be put forward for further review due to a request from the FCC or as a result of a relative undergoing testing, and that in most instances where a potential reclassification could occur based on updated information and/or classification methods, this opportunity is missed. Only two of the six surveyed laboratories indicated that they initiate their own variant re-review on a regular basis. Resources was the unanimous reason for no more regular or initiated variant re-review, and all but one of the laboratories noted that they would prioritise VUS review if they had more funding to do so. One laboratory representative elaborated that regular VUS review, regardless of the funding, requires significant consideration of the downstream clinical interactions and interventions. There are possible legal implications if there have been active clinical interventions due to classification as P/LP, such as prophylactic mastectomy and oophorectomy, with subsequent downgrades, or clinical inaction contributing even to deaths due to classifications as LB or VUS with subsequent upgrades, even within the same families. These results are a prompt to consider how a more effective and reliable process could be implemented for identifying reclassifiable VUS in clinical datasets and communicating updated curations to facilitate optimal care for patients. A simple and affordable recommendation to streamline the VUS review process between clinical services and laboratories is to promote automated notifications to the laboratories of Expert Panel reclassifications for variants within their curation system. In Australia, there is potential to facilitate this by leveraging the properties of Shariant ( 23 ), a system for real-time sharing of variant data between Australian FCCs and laboratories, which has recently introduced this capability. This could be supplemented by general look-ups to ClinVar, preferably in an automated manner as recently proposed ( 24 ). Ideally, this approach would be coupled with encouraging proactive notification of reclassifications by laboratories to FCCs. However, Expert Panels do not typically perform large-scale reviews of variants, as this typically exceeds the capacity of the VCEPs and is not prioritised by ClinGen, which usually focuses on variants with multiple uncertain or conflicting submissions. Therefore, while this "ClinVar notification" approach can be beneficial, it will not address the larger number of variants that are not reviewed by Expert Panels but would still benefit from more frequent laboratory-based reviews following gene-specific ACMG/AMP guidelines. There was no clear consensus in the survey responses around which group bears the final responsibility for the task of continuing review of VUS to identify potential reclassifications. A more comprehensive solution is required for promoting periodic laboratory review of VUS for potential increased actionability. Overall, our VUS review work revealed a potential pathogenic reclassification for over 4% of unique variants in selected hereditary cancer genes currently recorded in clinical databases as VUS. We expect that this reclassification rate would be greater with inclusion of evidence held privately within laboratories. The reclassification rate is also likely to increase with evolution of ClinGen gene-specific classification guidelines, which has been demonstrated in several VCEP-related studies to reduce the VUS rate ( 25 – 27 ). Regular VUS review and variant reclassification will require resources, adding to the routine work of trained staff. Numerous studies have demonstrated the cost-effectiveness of genetic testing in women with breast cancer ( 28 – 30 ). In response, countries such as Australia and the UK have integrated genetic testing for hereditary breast cancer risk into their respective government funded health services (Medicare and the NHS), targeting patients meeting specific eligibility criteria, including those with a 10% risk of carrying a germline pathogenic variant based on clinical presentation. It should be noted that VUS review and variant reclassification activities to identify a P/LP variant should be less costly than the initial genetic testing that incurred the costs of the initial consultation, sample collection, laboratory analysis, sequencing bioinformatics. Costs associated with VUS review would be limited to resources for re-curation costs, and re-issue of reports when necessary. Additionally, reclassifying VUS as B/LB (79% reclassification rate as per our work) has the potential to lead to savings by avoiding the cost of unnecessary clinical interventions, recognising that not all VUS are considered clinically relevant and management might be dependent on other factors, and by removing variants from the list of VUS requiring ongoing review by the laboratory. Further, for VUS previously returned to patients, there is potential to provide reassurance and relieve anxiety following a B/LB reclassification. Therefore, publicly funding the VUS review process in countries where hereditary cancer testing is already publicly funded appears likely to have economic benefits. In terms of VUS review frequency, two of the laboratories reported conducting this activity every 1–2 years, aligning with reported most effective frequencies ( 31 , 32 ). The inconsistency in approaches between diagnostic laboratories reveals a need to develop a national approach to standardise variant reclassification protocols. The consensus framework on variant reclassification developed by CanVIG-UK ( 33 ) might provide a useful starting point in this regard. Future directions of this work include assessing the clinical impact of our findings, and the cost-effectiveness of implementing routine variant review and reclassification practices. In parallel, national efforts should be directed towards promoting collaboration between FCCs and laboratories to ensure timely notification processes, potentially through standardised protocols and increased communication channels. Declarations Data Availability Statement Numerous data are made available via supplementary materials. Additional data can be made available on reasonable request. Author Contribution Statement CF assisted with methodology, analysed data and wrote the first draft of the manuscript. EJP assisted with data acquisition and coordination. ALD, JH, GI, MEM, and MP assisted with data analysis. AMC, AD, VF, MJF, HGMF, CBN, NKP, LW, and RW provided data and/or answered the survey. VB, CE, AJ, MM, VSK, RS, and MW answered or assisted with answering the survey. HS assisted with methodology and answered the survey. PAJ assisted with methodology, answered the survey, supervised CF and critically reviewed the manuscript. ABS conceived the project and acquired funding, designed the methodology, supervised CF and critically reviewed the manuscript. All authors read and provided input for the final version of the manuscript. Ethical Approval This project has been approved by the QIMR Berghofer Medical Research Institute Human Research Ethics Committee (HREC) under QIMR HREC Approval P1051. Competing Interests The authors declare no competing interests. References Larsen MJ, Thomassen M, Gerdes AM, Kruse TA. Hereditary breast cancer: clinical, pathological and molecular characteristics. Breast Cancer (Auckl). 2014;8:145–55. Mehrgou A, Akouchekian M. The importance of BRCA1 and BRCA2 genes mutations in breast cancer development. Med J Islam Repub Iran. 2016;30:369. Adedokun B, Zheng Y, Ndom P, Gakwaya A, Makumbi T, Zhou AY, et al. Prevalence of Inherited Mutations in Breast Cancer Predisposition Genes among Women in Uganda and Cameroon. Cancer Epidemiol Biomarkers Prev. 2020;29(2):359–67. Daly MB, Pal T, Maxwell KN, Churpek J, Kohlmann W, AlHilli Z, et al. NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2024. J Natl Compr Canc Netw. 2023;21(10):1000–10. Blondeaux E, Arecco L, Punie K, Graffeo R, Toss A, De Angelis C, et al. Germline TP53 pathogenic variants and breast cancer: A narrative review. Cancer treatment reviews. 2023;114:102522. Huszno J, Kołosza Z, Grzybowska E. BRCA1 mutation in breast cancer patients: Analysis of prognostic factors and survival. Oncol Lett. 2019;17(2):1986–95. Amano Y, Raz A, Timmermans S, Shkedi-Rafid S. Cancer patients' understandings of genetic variants of uncertain significance in clinical care. Journal of community genetics. 2022;13(4):381–8. Makhnoon S, Shirts BH, Bowen DJ. Patients' perspectives of variants of uncertain significance and strategies for uncertainty management. J Genet Couns. 2019;28(2):313–25. Chang EY, Solomon I, Culver JO, Gorman N, Comeaux JG, Lerman C, et al. Clinical and laboratory genetic counselor attitudes on the reporting of variants of uncertain significance for multigene cancer panels. J Genet Couns. 2023;32(3):706–16. Beard C, Monohan K, Cicciarelli L, James PA. Mainstream genetic testing for breast cancer patients: early experiences from the Parkville Familial Cancer Centre. Eur J Hum Genet. 2021;29(5):872–80. Makhnoon S, Levin B, Ensinger M, Mattie K, Volk RJ, Zhao Z, et al. A multicenter study of clinical impact of variant of uncertain significance reclassification in breast, ovarian and colorectal cancer susceptibility genes. Cancer Med. 2023;12(3):2875–84. Tsai GJ, Rañola JMO, Smith C, Garrett LT, Bergquist T, Casadei S, et al. Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance. Genetics in medicine: official journal of the American College of Medical Genetics. 2019;21(6):1435–42. So MK, Jeong TD, Lim W, Moon BI, Paik NS, Kim SC, et al. Reinterpretation of BRCA1 and BRCA2 variants of uncertain significance in patients with hereditary breast/ovarian cancer using the ACMG/AMP 2015 guidelines. Breast Cancer. 2019;26(4):510–9. Innella G, Ferrari S, Miccoli S, Luppi E, Fortuno C, Parsons MT, et al. Clinical implications of VUS reclassification in a single-centre series from application of ACMG/AMP classification rules specified for BRCA1/2. Journal of medical genetics. 2024;61(5):483–9. Ha HI, Ryu JS, Shim H, Kong SY, Lim MC. Reclassification of BRCA1 and BRCA2 variants found in ovarian epithelial, fallopian tube, and primary peritoneal cancers. Journal of gynecologic oncology. 2020;31(6):e83. Li D, Shi Y, Li A, Cao D, Su H, Yang H, et al. Retrospective reinterpretation and reclassification of BRCA1/2 variants from Chinese population. Breast Cancer. 2020;27(6):1158–67. Liu Y, Wang H, Wang X, Liu J, Li J, Wang X, et al. Prevalence and reclassification of BRCA1 and BRCA2 variants in a large, unselected Chinese Han breast cancer cohort. J Hematol Oncol. 2021;14(1):18. Lefter M, Vis JK, Vermaat M, den Dunnen JT, Taschner PEM, Laros JFJ. Mutalyzer 2: next generation HGVS nomenclature checker. Bioinformatics. 2021;37(18):2811–7. Chen S, Francioli LC, Goodrich JK, Collins RL, Kanai M, Wang Q, et al. A genomic mutational constraint map using variation in 76,156 human genomes. Nature. 2024;625(7993):92–100. Walker LC, Hoya M, Wiggins GAR, Lindy A, Vincent LM, Parsons MT, et al. Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup. Am J Hum Genet. 2023;110(7):1046–67. Tavtigian SV, Harrison SM, Boucher KM, Biesecker LG. Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines. Human mutation. 2020. Makhnoon S, Davidson E, Shirts B, Arun B, Shete S. Practices and Views of US Oncologists and Genetic Counselors Regarding Patient Recontact After Variant Reclassification: Results of a Nationwide Survey. JCO Precis Oncol. 2023;7:e2300079. Tudini E, Andrews J, Lawrence DM, King-Smith SL, Baker N, Baxter L, et al. Shariant platform: Enabling evidence sharing across Australian clinical genetic-testing laboratories to support variant interpretation. Am J Hum Genet. 2022;109(11):1960–73. Li L, Tian X, Woodzell V, Gibbs RA, Yuan B, Venner E. Tracking updates in clinical databases increases efficiency for variant reanalysis. Genetics in Medicine Open. 2024:101841. Fortuno C, Lee K, Olivier M, Pesaran T, Mai PL, de Andrade KC, et al. Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants. Human mutation. 2021;42(3):223–36. Mester JL, Ghosh R, Pesaran T, Huether R, Karam R, Hruska KS, et al. Gene-specific criteria for PTEN variant curation: Recommendations from the ClinGen PTEN Expert Panel. Human mutation. 2018;39(11):1581–92. Luo X, Maciaszek JL, Thompson BA, Leong HS, Dixon K, Sousa S, et al. Optimising clinical care through CDH1-specific germline variant curation: improvement of clinical assertions and updated curation guidelines. Journal of medical genetics. 2023;60(6):568–75. Tuffaha HW, Mitchell A, Ward RL, Connelly L, Butler JRG, Norris S, et al. Cost-effectiveness analysis of germ-line BRCA testing in women with breast cancer and cascade testing in family members of mutation carriers. Genetics in medicine: official journal of the American College of Medical Genetics. 2018;20(9):985–94. Koldehoff A, Danner M, Civello D, Rhiem K, Stock S, Müller D. Cost-Effectiveness of Targeted Genetic Testing for Breast and Ovarian Cancer: A Systematic Review. Value Health. 2021;24(2):303–12. Sun L, Brentnall A, Patel S, Buist DSM, Bowles EJA, Evans DGR, et al. A Cost-effectiveness Analysis of Multigene Testing for All Patients With Breast Cancer. JAMA Oncol. 2019;5(12):1718–30. Davidson AL, Kondrashova O, Leonard C, Wood S, Tudini E, Hollway GE, et al. Analysis of hereditary cancer gene variant classifications from ClinVar indicates a need for regular reassessment of clinical assertions. Human mutation. 2022;43(12):2054–62. Walsh N, Cooper A, Dockery A, O'Byrne JJ. Variant reclassification and clinical implications. Journal of medical genetics. 2024;61(3):207–11. Loong L, Garrett A, Allen S, Choi S, Durkie M, Callaway A, et al. Reclassification of clinically-detected sequence variants: Framework for genetic clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group UK). Genetics in medicine: official journal of the American College of Medical Genetics. 2022;24(9):1867–77. Additional Declarations There is no duality of interest Supplementary Files SupplementaryTable1.xlsx Cite Share Download PDF Status: Published Journal Publication published 14 Oct, 2024 Read the published version in European Journal of Human Genetics → Version 1 posted Editorial decision: revise 27 Jun, 2024 Review # 2 received at journal 26 Jun, 2024 Reviewer # 2 agreed at journal 13 Jun, 2024 Review # 1 received at journal 22 May, 2024 Reviewer # 1 agreed at journal 19 May, 2024 Reviewers invited by journal 14 May, 2024 Submission checks completed at journal 01 May, 2024 Editor assigned by journal 01 May, 2024 First submitted to journal 01 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4352556","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":302464517,"identity":"ffa2efc4-237b-4521-bfa0-666e018aaf78","order_by":0,"name":"Amanda Spurdle","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABY0lEQVRIie3RPUvDQBgH8CcErkskm1wJ/Q4tgabSYr7KHYXLUosgSIdYMt1U2rWi4lfoJAgOgUBcqm5SyGBEyNShIhQHKV4aI01od8H8h3vg7n489wJQpMgfDIoHBcCMKw6hFc+sJwnIblzlPFF/CHViQoBtEES2krKTkPWqIN5v652k+uxF4dwGYuCj1xnpPVWG+w9R+H531lWR7C+g16ROaVrdJAEzapc+mAdjS2+QaaBzzTJq4+j+pMxRewxTizpKJ0tIXVMQSJMZQ5jygHKNIU1xfTp5GeggcU9cM0PMwFpqyiolq8eEfMXEVz9AWgmizrNdOnVtj6fEcRMCri2IIoPkCIJzB+uclq+GmN4OIrlB/La4CyvVBq5LzznSgfiWznF0nCHWDZ4vW6ZRYtJsYR9Wri8YCj/dPh0h+Q0WdrMyUtuT/EuLH4G0teQk1UsKSb9pS/Kkv2NfkSJFivzDfAM/VH/rewi8/wAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-1337-7897","institution":"QIMR Berghofer Medical Research Institute","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Amanda","middleName":"","lastName":"Spurdle","suffix":""},{"id":302464518,"identity":"c277d482-d8b0-41eb-ade6-94bdbeba080c","order_by":1,"name":"Cristina Fortuno","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Cristina","middleName":"","lastName":"Fortuno","suffix":""},{"id":302464519,"identity":"ec8b7b36-7c8d-420e-9e9c-db39546d0e73","order_by":2,"name":"Elisa Cops","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Elisa","middleName":"","lastName":"Cops","suffix":""},{"id":302464520,"identity":"56ab8cc3-c34b-4457-95be-8b0bdcc7dee9","order_by":3,"name":"Aimee Davidson","email":"","orcid":"https://orcid.org/0000-0001-5034-5996","institution":"QIMR Berghofer Medical Research Institute","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Aimee","middleName":"","lastName":"Davidson","suffix":""},{"id":302464521,"identity":"8bd6aae9-8c51-479a-aece-ba09b63573d1","order_by":4,"name":"Johanna Hadler","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Johanna","middleName":"","lastName":"Hadler","suffix":""},{"id":302464522,"identity":"789391ef-20b6-4502-86e8-69d484783f60","order_by":5,"name":"Giovanni Innella","email":"","orcid":"https://orcid.org/0000-0002-6909-2412","institution":"Università di Bologna","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Giovanni","middleName":"","lastName":"Innella","suffix":""},{"id":302464523,"identity":"2f125974-5d03-4e30-b1a3-131c50599f6a","order_by":6,"name":"Maddison McKenzie","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Maddison","middleName":"","lastName":"McKenzie","suffix":""},{"id":302464524,"identity":"50bfbc9b-5d15-48f7-9dda-3ee7d7af913a","order_by":7,"name":"Michael Parsons","email":"","orcid":"https://orcid.org/0000-0003-3242-8477","institution":"QIMR Berghofer Medical Research Institute","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Parsons","suffix":""},{"id":302464525,"identity":"9e365a2d-b90a-4697-a599-5e774740cd46","order_by":8,"name":"Ainsley Campbell","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ainsley","middleName":"","lastName":"Campbell","suffix":""},{"id":302464526,"identity":"74310e18-5e51-4822-8341-c2a8fffdcd50","order_by":9,"name":"Andrew Dubowsky","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Andrew","middleName":"","lastName":"Dubowsky","suffix":""},{"id":302464527,"identity":"7f4681cd-6dee-4dc0-8271-34bc116fc66b","order_by":10,"name":"Verna Fargas","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Verna","middleName":"","lastName":"Fargas","suffix":""},{"id":302464528,"identity":"2fbb1463-fb21-4c04-899a-6eb6a391490f","order_by":11,"name":"Michael Field","email":"","orcid":"https://orcid.org/0000-0001-7455-934X","institution":"GOLD (Genetics of Learning Disability) service","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Field","suffix":""},{"id":302464529,"identity":"23710f61-4bca-405e-b432-7e3051035c65","order_by":12,"name":"Helen Mar Fan","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Helen","middleName":"Mar","lastName":"Fan","suffix":""},{"id":302464530,"identity":"de3b4a5a-8702-4793-803f-b7eae2029700","order_by":13,"name":"Cassandra Dowson","email":"","orcid":"","institution":"Genetic Services of Western Australia","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Cassandra","middleName":"","lastName":"Dowson","suffix":""},{"id":302464531,"identity":"9bcb8a88-99e5-4bab-8f6a-f94c284835b3","order_by":14,"name":"Nicola Poplawski","email":"","orcid":"https://orcid.org/0000-0002-9372-3325","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nicola","middleName":"","lastName":"Poplawski","suffix":""},{"id":302464532,"identity":"904d7b9e-6844-4457-8429-c8385e721134","order_by":15,"name":"Linda Warwick","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Linda","middleName":"","lastName":"Warwick","suffix":""},{"id":302464533,"identity":"6222ccd3-4072-4c0d-b341-b6d9a46e94c0","order_by":16,"name":"Rachel Williams","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rachel","middleName":"","lastName":"Williams","suffix":""},{"id":302464534,"identity":"e0289e74-92b4-4b73-bb9d-3de341cf1594","order_by":17,"name":"Victoria Beshay","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Victoria","middleName":"","lastName":"Beshay","suffix":""},{"id":302464535,"identity":"1be3a491-6bbb-4123-aa3d-9f81700f019f","order_by":18,"name":"Caitlin Edwards","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Caitlin","middleName":"","lastName":"Edwards","suffix":""},{"id":302464536,"identity":"630f46ec-d042-4ffb-a714-a6ce5a68f316","order_by":19,"name":"Andrea Johns","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Andrea","middleName":"","lastName":"Johns","suffix":""},{"id":302464537,"identity":"dab7259a-e96a-49d5-aede-78feeea212b6","order_by":20,"name":"Mary McPhillips","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mary","middleName":"","lastName":"McPhillips","suffix":""},{"id":302464538,"identity":"d9c6270b-f1c1-4290-a825-533634859d82","order_by":21,"name":"Vanessa Kumar","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Vanessa","middleName":"","lastName":"Kumar","suffix":""},{"id":302464539,"identity":"69c824e7-fb58-4d5b-8ef0-ac567ae2600e","order_by":22,"name":"Rodney Scott","email":"","orcid":"","institution":"University of Newcastle and the Hunter Medical Research Institute","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rodney","middleName":"","lastName":"Scott","suffix":""},{"id":302464540,"identity":"e34a4d15-fb8a-4ca4-820e-120e946068fd","order_by":23,"name":"Mark Williams","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mark","middleName":"","lastName":"Williams","suffix":""},{"id":302464541,"identity":"ca1c9b82-9c3b-463c-8ff3-c4aa5d912e39","order_by":24,"name":"Hamish SCOTT","email":"","orcid":"https://orcid.org/0000-0002-5813-631X","institution":"[email protected]","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hamish","middleName":"","lastName":"SCOTT","suffix":""},{"id":302464542,"identity":"b5d27852-3cc4-4978-b6fb-6e70515817c8","order_by":25,"name":"Paul James","email":"","orcid":"https://orcid.org/0000-0002-4361-4657","institution":"Peter MacCallum Cancer Centre","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Paul","middleName":"","lastName":"James","suffix":""},{"id":302464543,"identity":"64513e78-b24b-48e9-85ef-fb07b36c74a5","order_by":26,"name":"Amanda Spurdle","email":"","orcid":"","institution":"Faculty of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Amanda","middleName":"","lastName":"Spurdle","suffix":""}],"badges":[],"createdAt":"2024-05-01 05:40:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4352556/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4352556/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41431-024-01705-9","type":"published","date":"2024-10-14T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":57299698,"identity":"484d256b-8ea8-4904-b895-20ebc6e1e8fd","added_by":"auto","created_at":"2024-05-28 21:10:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":239108,"visible":true,"origin":"","legend":"\u003cp\u003eProportion of germline variants according to ClinVar-designated summary classification for breast cancer genes commonly included in multigene panels (as at 21 April 2024): \u003cem\u003eBRCA1\u003c/em\u003e(n=12,503 variants), \u003cem\u003eBRCA2\u003c/em\u003e (n= 18,921 variants), \u003cem\u003eCDH1\u003c/em\u003e (n= 4,500 variants), \u003cem\u003ePALB2\u003c/em\u003e(n= 6,081variants), \u003cem\u003ePTEN\u003c/em\u003e (n= 3,582 variants), and \u003cem\u003eTP53\u003c/em\u003e(n= 3,450 variants)\u003c/p\u003e\n\u003cp\u003eAbbreviations: B/LB = Benign/Likely benign; P/LP = Pathogenic/Likely pathogenic; VUS = Variant of uncertain significance\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4352556/v1/ed53689a9954342c3c94f412.png"},{"id":57299701,"identity":"174a8e1e-8102-4cca-b474-65afa7aa9c35","added_by":"auto","created_at":"2024-05-28 21:10:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":235829,"visible":true,"origin":"","legend":"\u003cp\u003eOverview of the process followed in this study to retrieve and review breast cancer VUS identified from FCC clinical databases for unrecognised actionability, and to understand processes limiting VUS review and reclassification\u003c/p\u003e\n\u003cp\u003eAbbreviations: ACMG/AMP = American College of Medical Genetics and Genomics/Association for Molecular Pathology; FCC = Familial cancer centre; VUS = Variant of uncertain significance\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4352556/v1/208534206608b4e0d4d556d4.png"},{"id":57299697,"identity":"baf6a146-8668-44d2-8270-43edfb500837","added_by":"auto","created_at":"2024-05-28 21:10:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":143114,"visible":true,"origin":"","legend":"\u003cp\u003eResults from the ClinVar crosscheck for 944 unique breast cancer VUS retrieved from FCCs according to the review status and designated summary classification\u003c/p\u003e\n\u003cp\u003eAbbreviations: B/LB = Benign/Likely benign; P/LP = Pathogenic/Likely pathogenic\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4352556/v1/9c51966f48f07f0c04ad9359.png"},{"id":57299703,"identity":"acd464d7-6a3d-411e-a840-dc718497d287","added_by":"auto","created_at":"2024-05-28 21:10:48","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":100945,"visible":true,"origin":"","legend":"\u003cp\u003eSuggested number of variant reclassifications as P/LP or B/LB out of the 698 VUS reviewed using gene-specific ACMG/AMP guidelines\u003c/p\u003e\n\u003cp\u003eAbbreviations: B/LB = Benign/Likely benign; P/LP = Pathogenic/Likely pathogenic\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4352556/v1/55fe8ee1f3c5662c4e528fa3.png"},{"id":66646934,"identity":"65ca734e-f28f-4974-b241-96e9a21262cc","added_by":"auto","created_at":"2024-10-15 07:05:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1146477,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4352556/v1/54f90617-2d19-4e7e-8239-13cdeab0695c.pdf"},{"id":57299700,"identity":"24e24721-30f9-4f51-a464-bf3b4d22f001","added_by":"auto","created_at":"2024-05-28 21:10:48","extension":"xlsx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":51760,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4352556/v1/080acfb55c514deccdd29e7e.xlsx"}],"financialInterests":"There is no duality of interest","formattedTitle":"Unrecognised actionability for breast cancer risk variants identified in a national-level review of Australian familial cancer centres","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBreast cancer is the most prevalent cancer diagnosed in women worldwide. The proportion of breast cancers in the general population attributed to \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e germline pathogenic variants is approximately 5\u0026ndash;10% (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), but this proportion is much higher (up to 55%) in selected families referred to familial cancer clinics (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Even though rarer than \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e, a short list of other highly penetrant genes are known to elevate breast cancer risk (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In general, hereditary breast cancer is associated with poorer survival rates compared to breast cancer as a whole (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGenetic testing is valuable as it provides patients and their close relatives with knowledge about their hereditary cancer risk, and guides personalised strategies for cancer prevention and treatment for both pathogenic variant carriers and those with \u0026ldquo;normal\u0026rdquo; results (no germline pathogenic variant identified). Multigene panel testing has been adopted as a cost-effective strategy to simultaneously sequence multiple genes, however these panels reveal variants of uncertain significance (VUS) more frequently than single gene testing approaches. Identification of VUS presents an important challenge to the clinical utility of precision genomic medicine (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). These variants not only limit effective clinical management but are also a source of anxiety and confusion for some clinicians, and for patients and their family members (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Presently, there are no definitive recommendations regarding the reporting of VUS, and attitudes on their disclosure vary among clinical and laboratory genetic counsellors (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTesting of breast cancer predisposition genes increased significantly in Australia following the introduction of national government funding of multigene panel testing in 2017. This is expected to have led to a corresponding increase in the number of breast cancer gene VUS identified. One Australian clinical genetic testing program employing multigene testing for breast cancer (covering \u003cem\u003eBRCA1, BRCA2, PALB2, TP53\u003c/em\u003e and \u003cem\u003eATM\u003c/em\u003e), reported a VUS detection rate of 8.7% (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), however the proportion of breast cancer gene variants reported as VUS in ClinVar, as at 21 April 2024, is notably higher. For the subset of genes whose testing is publicly funded in Australia (\u003cem\u003eBRCA1, BRCA2, CDH1, PALB2, PTEN, TP53\u003c/em\u003e), the VUS rate in ClinVar ranges from 16% to (\u003cem\u003eBRCA1\u003c/em\u003e) to 47% (\u003cem\u003eCDH1\u003c/em\u003e) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Furthermore, when variants with conflicting classifications are taken into account, these two categories collectively constitute at least a third of all variants in each gene.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eVUS reclassification has potential to alter clinical management in hereditary cancer patients (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), however little is known about the prevalence and potential for VUS reclassifications among breast cancer patients. The rate of VUS reclassification from purposeful variant reclassification efforts using American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines was 61% for a study of 92 patients with any VUS received through clinical testing (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), with ranges of up to 81.3% for \u003cem\u003eBRCA1/2\u003c/em\u003e-focused studies (\u003cspan additionalcitationids=\"CR14 CR15 CR16\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). It is therefore reasonable to think that reclassification of VUS in breast cancer risk genes has potential to improve patient clinical management.\u003c/p\u003e \u003cp\u003eThe aim of this project was to identify the scope of the problem of breast cancer VUS in Australian familial cancer centres (FCCs), and to understand reclassification processes and interaction between FCCs and diagnostic laboratories, in order to consider future strategies for increased actionability and improved clinical management of breast cancer patients.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eAn overview of the study process is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData acquisition\u003c/h2\u003e \u003cp\u003eWe engaged with 11 Australian FCCs participating in the Inherited Cancer Connect (ICCon) partnership (Forrest, 2018) to retrieve the breast cancer gene variants listed as VUS in their internal databases in the following genes eligible for publicly-funded testing in Australia: \u003cem\u003eBRCA1, BRCA2, CDH1, PALB2, PTEN\u003c/em\u003e, and \u003cem\u003eTP53\u003c/em\u003e. The participating FCCs were: ACT Genetic Service, Austin Health, the Adult Genetics Unit (a state-wide service for South Australia), Genetic Health Queensland, Genetic Health WA, Liverpool Cancer Genetics, Peter MacCallum Cancer Centre, Princes of Wales Hospital, Royal Melbourne Hospital, Royal North Shore, and St. George Hospital. Data retrieved corresponded to VUS results for patients undergoing multigene panel testing due to hereditary cancer risk identified post-2017 and up to 2022.\u003c/p\u003e \u003cp\u003eFor the six selected genes, we received VUS results from 1,516 patients. We first checked for nomenclature errors using the Mutalyzer tool (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Entries for 44 patients were unresolvable and were excluded. The nomenclature for the remaining entries was standardized as per HGVS recommendations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eClinVar crosscheck and groupings\u003c/h2\u003e \u003cp\u003eTo ascertain the extent to which variants labelled as \"VUS\" in FCC internal databases may have resulted from outdated or inadequately reassessed historical reports, we initially examined their classifications in ClinVar (as at 1 September 2022). These variants were categorised into four distinct groups, as follows:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eVariants with Expert Panel submissions as Likely pathogenic and Pathogenic (hereafter referred to as P/LP) or Likely benign and Benign (hereafter referred to as B/LB)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eVariants with multiple non-conflicting submissions as P/LP or B/LB\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eVariants with a single submission as P/LP or B/LB\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eVariants not belonging to any of these groups (i.e. variants with conflicting submissions, variants classified as Uncertain, and variants not previously submitted to ClinVar), hereafter referred to as \u0026ldquo;Other\u0026rdquo;\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eGene-specific ACMG/AMP guidelines application\u003c/h2\u003e \u003cp\u003eWe applied gene-specific ACMG/AMP criteria to variants in the \u0026ldquo;Other\u0026rdquo; ClinVar group, using the following criteria specifications versions: BRCA1 v1.1.0, BRCA2 v1.1.0, CDH1 v3.1.0, PALB2 v1.1.0, PTEN v3.0.0, and TP53 v1.4.0. Details for specifications are available in the ClinGen Criteria Specification Registry (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://cspec.genome.network/cspec/ui/svi/\u003c/span\u003e\u003cspan address=\"https://cspec.genome.network/cspec/ui/svi/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). For the population-based codes (BA1, BS1, PM2), we used the gnomAD v4.0 database (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), except for BRCA1 and BRCA2 for which we performed this step prior to v4.0 release, and whose latest guidelines specify the use of gnomAD v2.1 and gnomAD v3.1 (non-cancer datasets). For all genes, the cutoffs used for SpliceAI splicing predictions were \u0026ge;\u0026thinsp;0.2 (predicted impact) and \u0026le;\u0026thinsp;0.1 (no predicted impact), as recommended by the ClinGen Sequence Variant Interpretation Splicing Subgroup (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). All other codes were assigned following the respective gene specifications. The proposed class following review was assigned based on a Bayesian point systems (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), which included reclassifying as LB variants with a total of -1 points where the only pathogenic code applied is PM2_Supporting, and there are at least two benign codes applied.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eSurveys to FCCs and diagnostic laboratories\u003c/h2\u003e \u003cp\u003eTo enhance comprehension of the VUS review process and the dynamics between FCCs and diagnostic laboratories in Australia, as well as to identify unmet clinical needs, we developed two surveys:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAn eight-question survey was sent to each FCC representative, totalling nine representatives from 11 FCCs. The survey aimed to gain insights into how FCCs become aware of VUS reclassifications, actions taken post-notification of VUS upgrades/downgrades, and reasons for failing to update their internal clinical database.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eA 13-question survey was sent to each laboratory designated as being used by the FCCs, totalling six representatives from six laboratories. This survey sought to understand the reasons prompting VUS review, the frequency and constraints of VUS review, how laboratories learn of new Expert Panel classifications and subsequent actions, notifications of reclassifications to FCCs, and perspectives on the significance of regular VUS review.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eBoth of these surveys comprised multiple-choice questions, all of which had an option to provide additional comments when considered relevant, as well as separate open-ended questions.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eVariant spectrum per gene and ClinVar group\u003c/h2\u003e \u003cp\u003eData was available from 1472 patient records for breast cancer gene variants from all 11 participating FCCs, corresponding to 944 unique variants recorded as \u0026ldquo;VUS\u0026rdquo; across the FCC internal databases. Of these, the number of VUS per gene was as follows: 522 in \u003cem\u003eBRCA2\u003c/em\u003e, 265 in \u003cem\u003eBRCA1\u003c/em\u003e, 104 in \u003cem\u003ePALB2\u003c/em\u003e, 37 in \u003cem\u003eTP53\u003c/em\u003e, 11 in \u003cem\u003ePTEN\u003c/em\u003e, and five in \u003cem\u003eCDH1\u003c/em\u003e.\u003c/p\u003e \u003cp\u003eAn overview of the results from the ClinVar crosscheck is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. At the time (1 September 2022), approximately 20% of the unique VUS had Expert Panel submissions as P/LP (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) and B/LB (175), while 5% had multiple non-conflicting submissions in the same directions (9 P/LP and 36 B/LB). Additionally, two VUS had a single submission as P/LP, while 13 had a single submission as B/LB. For each gene, most of the VUS were in the \u0026ldquo;Other\u0026rdquo; group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eResults from the ClinVar crosscheck were returned to FCC representatives prior to the surveys for consideration of possible reclassification review, in particular variants with ClinVar assertions apart from VUS from Expert Panels or with multiple non-conflicting submissions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eGene-specific ACMG/AMP application\u003c/h2\u003e \u003cp\u003e We applied gene-specific ACMG/AMP guidelines to all the VUS in the \u0026ldquo;Other\u0026rdquo; ClinVar group (total 698 variants). The number of our resulting proposed reclassifications per gene is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. There was no suggested reclassification for three \u003cem\u003eCDH1\u003c/em\u003e variants. Application of the specifications for the remaining genes overall reclassified 3% of all variants as P/LP (19 out of the 698 \u0026ldquo;Other\u0026rdquo; VUS), and 77% variants as B/LB (534). These variants, codes applied, and our suggested classification are detailed in Supplementary Table\u0026nbsp;1. As an update, we added updated ClinVar classification details (as at 27 January 2024).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eResults from FCC survey\u003c/h2\u003e \u003cp\u003eWe received survey results from representatives of all 11 participating FCCs, with some clinicians answering on behalf of multiple centres. A simplified summary of key survey results is shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of relevant responses from the FCC survey by nine representatives*\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; How FCCs report to become aware of VUS reclassifications\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Laboratory/s routinely inform them of VUS upgrades (VUS to P/LP) for reports of existing patients (4/9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Laboratory/s routinely inform them of VUS downgrades (VUS to B/LB) for reports of existing patients (3/9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- There is a diagnostic report for a new patient with the same variant (3/9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Regular review of variants in internal clinical database (2/9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Other: review with the laboratory when patients contacts for more information (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), referral of a relative (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), local and/or national MDT meetings (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Clinical actions taken by FCCs after VUS reclassifications\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- VUS upgrades: Request re-issue of a report for patients with an alternative pre-existing classification (9/9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- VUS downgrades: Request re-issue of a report for patients with an alternative pre-existing classification (6/9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Reasons for not updating internal clinical database\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Not being aware of a VUS reclassification (8/9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Lack of resources (3/9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Not clinically necessary (1/9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"1\"\u003e*Responses without the denominator noted (\u0026ldquo;/\u0026rdquo;) refer to open-ended questions\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"1\"\u003eAbbreviations: B/LB\u0026thinsp;=\u0026thinsp;Benign/Likely benign; FCC\u0026thinsp;=\u0026thinsp;Familial cancer centre; MDT\u0026thinsp;=\u0026thinsp;Multidisciplinary team; P/LP\u0026thinsp;=\u0026thinsp;Pathogenic/Likely pathogenic; VUS\u0026thinsp;=\u0026thinsp;Variant of uncertain significance\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegarding how FCCs become aware of VUS reclassifications, four of the nine FCC representatives reported that their laboratory provider routinely notifies them of VUS upgrades, while this number decreased to three for downgrades. Other methods selected were receiving a diagnostic report for a new patient with the same variant (3/9) and conducting regular reviews of variants within their internal clinical database (2/9). Additionally, some FCC representatives provided free-text responses citing additional reasons such as patients reaching out for more information (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), referral of a relative (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), and involvement in local and/or national multidisciplinary team (MDT) meetings (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAs per actions taken upon VUS reclassifications, it was found that all participating FCCs requested the re-issue of reports for patients in cases of VUS upgrades, whereas only six out of nine FCC representatives did so for variant downgrades.\u003c/p\u003e \u003cp\u003eLastly, the majority of FCC representatives reported that the primary reason for the lack of updates in their internal clinical databases was their unawareness of VUS reclassifications (8/9), with a lack of resources also cited as a contributing factor by a third of the representatives (3/9), and not considered clinically necessary by one representative (1/9).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eResults from laboratory survey\u003c/h2\u003e \u003cp\u003eWe received survey results from representatives of all six participating laboratories. A summary of the responses regarding activities prompting review of previously identified VUS is presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, with a scale provided from 1 (least often) to 5 (most often) for the activities considered relevant by the laboratories.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of activities most commonly prompting VUS review as reported by six laboratory representatives\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eActivity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eScale from 1 (least often) to 5 (most often)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAverage*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLab 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLab 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLab 3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLab 4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLab 5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLab 6\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFCC/clinician\u0026nbsp;contacts the lab for more/updated information\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe laboratory identifies new evidence (clinical, functional etc.) for a specific variant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFCC/clinician provides information to justify variant re-review\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNew classification guidelines/recommendations\u0026nbsp;become available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegular VUS review as part of the laboratory SOP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA new evidence type/algorithm is included in the lab SOP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNew ClinVar Expert Panel submissions\u0026nbsp;are available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNew ClinVar laboratory or research submissions are available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe laboratory generates or accesses external research findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e*The scale of activities not considered relevant, marked with a \u0026ldquo;-\u0026rdquo;, was counted as 0 for average calculations\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eAbbreviations: FCC\u0026thinsp;=\u0026thinsp;Familial cancer centre; VUS\u0026thinsp;=\u0026thinsp;Variant of uncertain significance\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe activity most commonly cited as prompting review was FCCs contacting laboratories for additional information (average rating of 3.83), followed by laboratories identifying new evidence (average rating of 3). Conversely, activities least likely to prompt VUS review included laboratories generating or accessing external research findings (average rating of 0.7), followed by the availability of new ClinVar submissions (average rating of 0.8).\u003c/p\u003e \u003cp\u003eA simplified summary of other key survey results from the six laboratory representatives is shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Only two out of six laboratories reported conducting regular reviews of VUS, one annually, the other at least biannually. Lack of resources was cited by all laboratories as a primary reason for not regularly conducting this activity. Additional reasons noted by half of the laboratories were an inability to track previous results for variants not included in reports, and the activity not deemed clinically relevant unless prompted by FCCs for additional information.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of other relevant responses from the diagnostic laboratory survey by six representatives*\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Frequency of VUS review\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Every 1 or 2 years (2/6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- No regular review (4/6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Reasons limiting regular VUS review\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Resources (6/6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Inability to track previous results for variants not included in reports (3/6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Not considered clinically relevant unless FCCs contact for more information (3/6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; How laboratories report to become aware of new Expert Panel reclassifications\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- By being members of ClinGen (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- No single established process (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Actions taken after laboratories become aware of a new Expert Panel reclassification\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Review and/or discuss the information provided (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Reclassify the variant (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Inform the relevant FCC (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Routine notification of reclassifications to the FCCs\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Yes for variant upgrades (6/6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Yes for variant downgrades (5/6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Existence of a documented process in place by which VUS reclassifications are notified to the FCCs\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Yes (5/6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Prioritisation of VUS regular review if there was more funding\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Yes (5/6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"1\"\u003e*Responses without the denominator noted (\u0026ldquo;/\u0026rdquo;) refer to open-ended questions\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"1\"\u003eAbbreviations: FCC\u0026thinsp;=\u0026thinsp;Familial cancer centre; VUS\u0026thinsp;=\u0026thinsp;Variant of uncertain significance\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegarding awareness of new Expert Panel reclassifications in an open-ended survey question, two out of the six laboratories indicated that they had easier access to these updates by virtue of being VCEP members, while the remaining laboratories lacked a standardised process.\u003c/p\u003e \u003cp\u003eAnother open-ended survey question revealed the following actions taken following new Expert Panel reclassifications, including: review and/or discussion of provided information for potential reclassification (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e); reclassification of relevant variants (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e); and informing the relevant FCC to request a reclassification from the lab (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWith regards to notifications to FCCs, all laboratories reported notifying FCCs of VUS upgrades, compared to five out of six for downgrades. One of the laboratories reporting notifications of both options added a note to clarify that these were expected actions, since they would only review VUS following a previous FCC enquiry. The majority of laboratories reported having a documented process in place for notifying FCCs of VUS reclassifications (5/6).\u003c/p\u003e \u003cp\u003eLastly, all laboratories except one indicated that VUS regular review would be prioritised if additional funding were available (5/6).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe have performed a nation-wide audit of VUS recorded in the clinical databases of Australian familial cancer services to determine the scale of unrecognised actionability, and to map the current and required processes to achieve effective variant review. Our ultimate aim is to inform future improvements in Australian practices concerning variant classification, reducing variant uncertainty and improving patient clinical management.\u003c/p\u003e \u003cp\u003eWith a straightforward crosscheck of the 944 clinically detected VUS retrieved from FCCs against ClinVar, we found that a notable number of the historical reports recorded in FCC internal clinical databases had not undergone updates and/or reassessment with existing new evidence. Approximately 20% of the so-called VUS had an Expert Panel submission as P/LP or B/LB, with an additional 5% exhibiting multiple non-conflicting submissions in the same categories, information that was returned to the FCCs. Most of these ClinVar submissions were in the benign direction, however there are many reasons to consider variant downgrades as clinically important, including the opportunity to avoid unnecessary clinical risk management interventions or relief from any continuing anxiety, although it can also be an indication to continue searching for alternative genetic explanations. According to the results from the survey of FCCs, the majority of reclassifications in either direction, specifically 100% of VUS upgrades and 67% of downgrades, would be communicated to patients. This attitude aligns with findings from a US-based survey study where both oncologists and genetic counsellors concurred that all reclassified variants, even when they do not represent a change in clinical management, should be disclosed to patients (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Of the greatest concern though were the 11 variants with Expert Panel submissions as P/LP, alongside nine variants with multiple non-conflicting P/LP submissions (collectively corresponding to 26 patients), which have a more clear-cut implication for the management of the patients and their family members.\u003c/p\u003e \u003cp\u003e For the large group of remaining variants that are VUS, conflicting in ClinVar or absent from the database altogether, we found that application of gene-specific guidelines developed by ClinGen Expert Panels resulted in a 79% reduction in the VUS rate, even when relying solely on publicly available information. Of the 698 variants in the \u0026ldquo;Other\u0026rdquo; ClinVar group (as at 1 September 2022), 3% (19 variants) could be reclassified as P/LP and 77% (534) as B/LB by the application of gene-specific guidelines. When added to the variants with Expert Panel or multiple non-conflicting submissions, our analysis suggests that a total of 4% of the initially provided 944 unique VUS (39 variants), could potentially be reclassified as P/LP, while more than three quarters of the VUS (745 out of 944, 79%) could be reclassified as B/LB utilising this approach.\u003c/p\u003e \u003cp\u003eTo better understand the factors contributing to these findings, and to describe the barriers to FCCs and laboratory identifying and implementing reclassifications, we surveyed both groups. Representatives from a large majority of FCCs (89%) indicated that they do not routinely update their internal variant database as they are generally not aware of any potential reclassifications. On the other hand, in the laboratory survey results, laboratories indicated that they notify the FCCs of variant reclassifications in nearly all instances, with the primary reason prompting VUS review being an FCC request to the laboratory for additional or updated information. This highlights a major flaw in the current VUS review process: FCCs heavily rely on laboratories to keep them updated of variant reclassifications, as they do not have the clinical capacity and/or expertise to do their own reviews, but laboratories rarely initiate VUS review without a clinical prompt. The results suggest that only a relatively low proportion of VUS found in patients will be put forward for further review due to a request from the FCC or as a result of a relative undergoing testing, and that in most instances where a potential reclassification could occur based on updated information and/or classification methods, this opportunity is missed. Only two of the six surveyed laboratories indicated that they initiate their own variant re-review on a regular basis. Resources was the unanimous reason for no more regular or initiated variant re-review, and all but one of the laboratories noted that they would prioritise VUS review if they had more funding to do so. One laboratory representative elaborated that regular VUS review, regardless of the funding, requires significant consideration of the downstream clinical interactions and interventions. There are possible legal implications if there have been active clinical interventions due to classification as P/LP, such as prophylactic mastectomy and oophorectomy, with subsequent downgrades, or clinical inaction contributing even to deaths due to classifications as LB or VUS with subsequent upgrades, even within the same families.\u003c/p\u003e \u003cp\u003eThese results are a prompt to consider how a more effective and reliable process could be implemented for identifying reclassifiable VUS in clinical datasets and communicating updated curations to facilitate optimal care for patients. A simple and affordable recommendation to streamline the VUS review process between clinical services and laboratories is to promote automated notifications to the laboratories of Expert Panel reclassifications for variants within their curation system. In Australia, there is potential to facilitate this by leveraging the properties of Shariant (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), a system for real-time sharing of variant data between Australian FCCs and laboratories, which has recently introduced this capability. This could be supplemented by general look-ups to ClinVar, preferably in an automated manner as recently proposed (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Ideally, this approach would be coupled with encouraging proactive notification of reclassifications by laboratories to FCCs. However, Expert Panels do not typically perform large-scale reviews of variants, as this typically exceeds the capacity of the VCEPs and is not prioritised by ClinGen, which usually focuses on variants with multiple uncertain or conflicting submissions. Therefore, while this \"ClinVar notification\" approach can be beneficial, it will not address the larger number of variants that are not reviewed by Expert Panels but would still benefit from more frequent laboratory-based reviews following gene-specific ACMG/AMP guidelines.\u003c/p\u003e \u003cp\u003eThere was no clear consensus in the survey responses around which group bears the final responsibility for the task of continuing review of VUS to identify potential reclassifications. A more comprehensive solution is required for promoting periodic laboratory review of VUS for potential increased actionability. Overall, our VUS review work revealed a potential pathogenic reclassification for over 4% of unique variants in selected hereditary cancer genes currently recorded in clinical databases as VUS. We expect that this reclassification rate would be greater with inclusion of evidence held privately within laboratories. The reclassification rate is also likely to increase with evolution of ClinGen gene-specific classification guidelines, which has been demonstrated in several VCEP-related studies to reduce the VUS rate (\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRegular VUS review and variant reclassification will require resources, adding to the routine work of trained staff. Numerous studies have demonstrated the cost-effectiveness of genetic testing in women with breast cancer (\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). In response, countries such as Australia and the UK have integrated genetic testing for hereditary breast cancer risk into their respective government funded health services (Medicare and the NHS), targeting patients meeting specific eligibility criteria, including those with a 10% risk of carrying a germline pathogenic variant based on clinical presentation. It should be noted that VUS review and variant reclassification activities to identify a P/LP variant should be less costly than the initial genetic testing that incurred the costs of the initial consultation, sample collection, laboratory analysis, sequencing bioinformatics. Costs associated with VUS review would be limited to resources for re-curation costs, and re-issue of reports when necessary. Additionally, reclassifying VUS as B/LB (79% reclassification rate as per our work) has the potential to lead to savings by avoiding the cost of unnecessary clinical interventions, recognising that not all VUS are considered clinically relevant and management might be dependent on other factors, and by removing variants from the list of VUS requiring ongoing review by the laboratory. Further, for VUS previously returned to patients, there is potential to provide reassurance and relieve anxiety following a B/LB reclassification. Therefore, publicly funding the VUS review process in countries where hereditary cancer testing is already publicly funded appears likely to have economic benefits. In terms of VUS review frequency, two of the laboratories reported conducting this activity every 1\u0026ndash;2 years, aligning with reported most effective frequencies (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). The inconsistency in approaches between diagnostic laboratories reveals a need to develop a national approach to standardise variant reclassification protocols. The consensus framework on variant reclassification developed by CanVIG-UK (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e) might provide a useful starting point in this regard.\u003c/p\u003e \u003cp\u003eFuture directions of this work include assessing the clinical impact of our findings, and the cost-effectiveness of implementing routine variant review and reclassification practices. In parallel, national efforts should be directed towards promoting collaboration between FCCs and laboratories to ensure timely notification processes, potentially through standardised protocols and increased communication channels.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNumerous data are made available via supplementary materials. Additional data can be made available on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCF assisted with methodology, analysed data and wrote the first draft of the manuscript. EJP assisted with data acquisition and coordination. ALD, JH, GI, MEM, and MP assisted with data analysis. AMC, AD, VF, MJF, HGMF, CBN, NKP, LW, and RW provided data and/or answered the survey. VB, CE, AJ, MM, VSK, RS, and MW answered or assisted with answering the survey. HS assisted with methodology and answered the survey. PAJ assisted with methodology, answered the survey, supervised CF and critically reviewed the manuscript.\u0026nbsp;ABS conceived the project and acquired funding, designed the methodology, supervised CF and critically reviewed the manuscript. All authors read and provided input for the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project has been approved by the QIMR Berghofer Medical Research Institute Human Research Ethics Committee (HREC) under QIMR HREC Approval P1051.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests. \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLarsen MJ, Thomassen M, Gerdes AM, Kruse TA. Hereditary breast cancer: clinical, pathological and molecular characteristics. Breast Cancer (Auckl). 2014;8:145\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMehrgou A, Akouchekian M. The importance of BRCA1 and BRCA2 genes mutations in breast cancer development. Med J Islam Repub Iran. 2016;30:369.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAdedokun B, Zheng Y, Ndom P, Gakwaya A, Makumbi T, Zhou AY, et al. Prevalence of Inherited Mutations in Breast Cancer Predisposition Genes among Women in Uganda and Cameroon. Cancer Epidemiol Biomarkers Prev. 2020;29(2):359\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDaly MB, Pal T, Maxwell KN, Churpek J, Kohlmann W, AlHilli Z, et al. NCCN Guidelines\u0026reg; Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2024. J Natl Compr Canc Netw. 2023;21(10):1000\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBlondeaux E, Arecco L, Punie K, Graffeo R, Toss A, De Angelis C, et al. Germline TP53 pathogenic variants and breast cancer: A narrative review. Cancer treatment reviews. 2023;114:102522.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuszno J, Kołosza Z, Grzybowska E. BRCA1 mutation in breast cancer patients: Analysis of prognostic factors and survival. Oncol Lett. 2019;17(2):1986\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmano Y, Raz A, Timmermans S, Shkedi-Rafid S. Cancer patients' understandings of genetic variants of uncertain significance in clinical care. Journal of community genetics. 2022;13(4):381\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMakhnoon S, Shirts BH, Bowen DJ. Patients' perspectives of variants of uncertain significance and strategies for uncertainty management. J Genet Couns. 2019;28(2):313\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChang EY, Solomon I, Culver JO, Gorman N, Comeaux JG, Lerman C, et al. Clinical and laboratory genetic counselor attitudes on the reporting of variants of uncertain significance for multigene cancer panels. J Genet Couns. 2023;32(3):706\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeard C, Monohan K, Cicciarelli L, James PA. Mainstream genetic testing for breast cancer patients: early experiences from the Parkville Familial Cancer Centre. Eur J Hum Genet. 2021;29(5):872\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMakhnoon S, Levin B, Ensinger M, Mattie K, Volk RJ, Zhao Z, et al. A multicenter study of clinical impact of variant of uncertain significance reclassification in breast, ovarian and colorectal cancer susceptibility genes. Cancer Med. 2023;12(3):2875\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTsai GJ, Ra\u0026ntilde;ola JMO, Smith C, Garrett LT, Bergquist T, Casadei S, et al. Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance. Genetics in medicine: official journal of the American College of Medical Genetics. 2019;21(6):1435\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSo MK, Jeong TD, Lim W, Moon BI, Paik NS, Kim SC, et al. Reinterpretation of BRCA1 and BRCA2 variants of uncertain significance in patients with hereditary breast/ovarian cancer using the ACMG/AMP 2015 guidelines. Breast Cancer. 2019;26(4):510\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInnella G, Ferrari S, Miccoli S, Luppi E, Fortuno C, Parsons MT, et al. Clinical implications of VUS reclassification in a single-centre series from application of ACMG/AMP classification rules specified for BRCA1/2. Journal of medical genetics. 2024;61(5):483\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHa HI, Ryu JS, Shim H, Kong SY, Lim MC. Reclassification of BRCA1 and BRCA2 variants found in ovarian epithelial, fallopian tube, and primary peritoneal cancers. Journal of gynecologic oncology. 2020;31(6):e83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi D, Shi Y, Li A, Cao D, Su H, Yang H, et al. Retrospective reinterpretation and reclassification of BRCA1/2 variants from Chinese population. Breast Cancer. 2020;27(6):1158\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Y, Wang H, Wang X, Liu J, Li J, Wang X, et al. Prevalence and reclassification of BRCA1 and BRCA2 variants in a large, unselected Chinese Han breast cancer cohort. J Hematol Oncol. 2021;14(1):18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLefter M, Vis JK, Vermaat M, den Dunnen JT, Taschner PEM, Laros JFJ. Mutalyzer 2: next generation HGVS nomenclature checker. Bioinformatics. 2021;37(18):2811\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen S, Francioli LC, Goodrich JK, Collins RL, Kanai M, Wang Q, et al. A genomic mutational constraint map using variation in 76,156 human genomes. Nature. 2024;625(7993):92\u0026ndash;100.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalker LC, Hoya M, Wiggins GAR, Lindy A, Vincent LM, Parsons MT, et al. Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup. Am J Hum Genet. 2023;110(7):1046\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTavtigian SV, Harrison SM, Boucher KM, Biesecker LG. Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines. Human mutation. 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMakhnoon S, Davidson E, Shirts B, Arun B, Shete S. Practices and Views of US Oncologists and Genetic Counselors Regarding Patient Recontact After Variant Reclassification: Results of a Nationwide Survey. JCO Precis Oncol. 2023;7:e2300079.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTudini E, Andrews J, Lawrence DM, King-Smith SL, Baker N, Baxter L, et al. Shariant platform: Enabling evidence sharing across Australian clinical genetic-testing laboratories to support variant interpretation. Am J Hum Genet. 2022;109(11):1960\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi L, Tian X, Woodzell V, Gibbs RA, Yuan B, Venner E. Tracking updates in clinical databases increases efficiency for variant reanalysis. Genetics in Medicine Open. 2024:101841.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFortuno C, Lee K, Olivier M, Pesaran T, Mai PL, de Andrade KC, et al. Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants. Human mutation. 2021;42(3):223\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMester JL, Ghosh R, Pesaran T, Huether R, Karam R, Hruska KS, et al. Gene-specific criteria for PTEN variant curation: Recommendations from the ClinGen PTEN Expert Panel. Human mutation. 2018;39(11):1581\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuo X, Maciaszek JL, Thompson BA, Leong HS, Dixon K, Sousa S, et al. Optimising clinical care through CDH1-specific germline variant curation: improvement of clinical assertions and updated curation guidelines. Journal of medical genetics. 2023;60(6):568\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTuffaha HW, Mitchell A, Ward RL, Connelly L, Butler JRG, Norris S, et al. Cost-effectiveness analysis of germ-line BRCA testing in women with breast cancer and cascade testing in family members of mutation carriers. Genetics in medicine: official journal of the American College of Medical Genetics. 2018;20(9):985\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKoldehoff A, Danner M, Civello D, Rhiem K, Stock S, M\u0026uuml;ller D. Cost-Effectiveness of Targeted Genetic Testing for Breast and Ovarian Cancer: A Systematic Review. Value Health. 2021;24(2):303\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun L, Brentnall A, Patel S, Buist DSM, Bowles EJA, Evans DGR, et al. A Cost-effectiveness Analysis of Multigene Testing for All Patients With Breast Cancer. JAMA Oncol. 2019;5(12):1718\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDavidson AL, Kondrashova O, Leonard C, Wood S, Tudini E, Hollway GE, et al. Analysis of hereditary cancer gene variant classifications from ClinVar indicates a need for regular reassessment of clinical assertions. Human mutation. 2022;43(12):2054\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalsh N, Cooper A, Dockery A, O'Byrne JJ. Variant reclassification and clinical implications. Journal of medical genetics. 2024;61(3):207\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLoong L, Garrett A, Allen S, Choi S, Durkie M, Callaway A, et al. Reclassification of clinically-detected sequence variants: Framework for genetic clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group UK). Genetics in medicine: official journal of the American College of Medical Genetics. 2022;24(9):1867\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-human-genetics","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ejhg","sideBox":"Learn more about [European Journal of Human Genetics](http://www.nature.com/ejhg/)","snPcode":"41431","submissionUrl":"https://mts-ejhg.nature.com/cgi-bin/main.plex","title":"European Journal of Human Genetics","twitterHandle":"@ejhg_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4352556/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4352556/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBreast cancer remains a significant global health challenge. In Australia, the adoption of publicly-funded multigene panel testing for eligible cancer patients has increased accessibility to personalised care, yet has also highlighted the increasing prevalence of variants of uncertain significance (VUS), complicating clinical decision-making. This project aimed to explore the spectrum and actionability of breast cancer VUS in Australian familial cancer centers (FCCs).\u003c/p\u003e \u003cp\u003eLeveraging data from 11 FCCs participating in the Inherited Cancer Connect database, we retrieved VUS results from 1472 patients. Through ClinVar crosschecks and application of gene-specific ACMG/AMP guidelines, we showed the potential for reclassification of 4% of unique VUS as pathogenic or likely pathogenic, and 79% as benign or likely benign. Surveys conducted with FCCs and diagnostic laboratories described current practices and challenges in variant reclassifications, highlighting resource constraints preventing periodic VUS review and notifications from the laboratories to the FCCs.\u003c/p\u003e \u003cp\u003eOur study suggests there are benefits to routine VUS review and reclassification, particularly in publicly-funded healthcare systems. Future research should focus on assessing the clinical impact and cost-effectiveness of implementing routine variant review practices, alongside efforts to enhance communication between FCCs and laboratories.\u003c/p\u003e","manuscriptTitle":"Unrecognised actionability for breast cancer risk variants identified in a national-level review of Australian familial cancer centres","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-28 21:10:43","doi":"10.21203/rs.3.rs-4352556/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-06-27T19:38:29+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-06-26T19:13:51+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-06-13T07:14:16+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-05-22T22:22:23+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-05-20T01:29:35+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-05-14T17:25:11+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-01T10:50:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-01T05:39:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Human Genetics","date":"2024-05-01T05:39:27+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-human-genetics","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ejhg","sideBox":"Learn more about [European Journal of Human Genetics](http://www.nature.com/ejhg/)","snPcode":"41431","submissionUrl":"https://mts-ejhg.nature.com/cgi-bin/main.plex","title":"European Journal of Human Genetics","twitterHandle":"@ejhg_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"7a401f14-6032-4bab-912f-1677507ed110","owner":[],"postedDate":"May 28th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":31915540,"name":"Biological sciences/Genetics/Clinical genetics/Cancer genetics"},{"id":31915541,"name":"Health sciences/Health care/Diagnosis/Genetic testing"}],"tags":[],"updatedAt":"2024-10-15T07:05:23+00:00","versionOfRecord":{"articleIdentity":"rs-4352556","link":"https://doi.org/10.1038/s41431-024-01705-9","journal":{"identity":"european-journal-of-human-genetics","isVorOnly":false,"title":"European Journal of Human Genetics"},"publishedOn":"2024-10-14 04:00:00","publishedOnDateReadable":"October 14th, 2024"},"versionCreatedAt":"2024-05-28 21:10:43","video":"","vorDoi":"10.1038/s41431-024-01705-9","vorDoiUrl":"https://doi.org/10.1038/s41431-024-01705-9","workflowStages":[]},"version":"v1","identity":"rs-4352556","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4352556","identity":"rs-4352556","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}