Case report: A rare BRCA1 de novo variant in a female with breast cancer

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While lifestyle factors contribute to rising incidence, 5–14% of cases result from pathogenic variants in core susceptibility genes such as BRCA1 , which also increases ovarian cancer risk and, in men, prostate cancer risk. BRCA1 variants are typically autosomal dominant, making family history a key criterion for genetic testing under guidelines like HBOC or NCCN. Although usually inherited, de novo BRCA1 mutations occur rarely; only twelve cases have been reported. We present a young woman with breast cancer without a significant family history, and a pathogenic de novo BRCA1 variant. Case Presentation We report a 37-year-old woman with HER2-positive, ER/PR-positive invasive breast cancer without relevant family history. After imaging-confirmed T1cN0M0 disease, she received neoadjuvant Her2-targeted chemotherapy, breast-conserving surgery, postneoadjuvant trastuzumab emtansine, radiotherapy, and ongoing endocrine therapy. Genetic testing by Next Generation Sequencing revealed a BRCA1 frameshift variant (NM_007294.4:c.1335_1336del, p.(Arg446Serfs*9)) which was classified as pathogenic per ENIGMA/ACMG guidelines. Absent from population databases and previously reported in cancer cases, it disrupts protein function. Cascade testing showed neither parent carried the variant; microsatellite analysis confirmed parentage, indicating a de novo mutation. Conclusion A rare de novo BRCA1 variant was identified in a young breast cancer patient. Such variants are likely underdiagnosed due to historical testing limitations and reliance on family history. This case highlights the importance of genetic testing and inclusion in hereditary cancer prevention programs, even without a family history. De novo breast cancer BRCA1 HBOC 1. Background Breast cancer is the most common malignancy among women worldwide, with an incidence of 47 per 100.000 women ( 1 ). Incidence rates are particularly increasing in Western countries, largely due to lifestyle factors, such as overweight, smoking, alcohol consumption, and hormonal influences ( 2 ). However, 5-14.1% of breast cancer cases are attributable to pathogenic genetic variants in common breast cancer genes, with pathogenic variants in the BRCA1 gene being a well-known cause ( 3 , 4 ). Pathogenic BRCA1 variants also increase the risk of ovarian cancer and, in men, prostate cancer and are inherited in an autosomal dominant manner. Consequently, these variants are frequently associated with a notable family history of the disease, and family history remains a central criterion for genetic testing. According to established guidelines (such as the HBOC (Hereditary breast and ovarian cancer) or NCCN (National Comprehensive Cancer Network) criteria ( 5 , 6 )), individuals undergo genetic testing if they meet specific clinical or familial risk factors, including early-onset breast cancer, triple-negative phenotype, bilateral disease, or a family history of breast or ovarian cancer. A genetically confirmed pathogenic variant in one of the breast cancer susceptibility genes (e.g. BRCA1 ) qualifies patients to participate in intensive early detection programs, which may include enhanced imaging surveillance and consideration of risk-reducing surgery, to facilitate early diagnosis or recurrence detection. Although most BRCA1 variants are inherited, de novo variants can occur. To date, only twelve cases of de novo BRCA1 variants have been reported in the literature, often identified in young patients with early-onset breast cancer and unremarkable family histories ( 7 – 16 ). In this case report, we describe another instance of a young woman with breast cancer who had no remarkable family history and was found to carry a pathogenic de novo BRCA1 variant. 2. Case Presentation 2.1 Patients Presentation We present a case study of a 37-year-old female patient who was diagnosed with an invasive carcinoma of the right breast in 2020. The family history was unremarkable with regard to genetic tumour predisposition syndromes, in particular breast and ovarian cancer (see Supplement Fig. S1 ). An initial ultrasound examination identified a tumour measuring 1.1 × 0.6 × 5.0 cm, a finding that was subsequently confirmed by magnetic resonance imaging. No additional lesions suggestive of metastatic disease were detected on imaging. The patient underwent neoadjuvant systemic therapy consisting of 12 cycles of paclitaxel combined with dual receptor blockade, followed by four cycles of epirubicin and cyclophosphamide chemotherapy. Surgical management entailed breast-conserving surgery (lumpectomy) with a sentinel lymph node biopsy. Histopathological evaluation revealed a tumour with 100% positivity for oestrogen receptor (ER) and progesterone receptor (PR). Human epidermal growth factor receptor 2 (HER2/neu) status was scored as 3 + by immunohistochemistry. The Ki-67 proliferation index was quantified at 35%. Tumour staging at diagnosis was clinical T1c N0 M0, with a histological grade of G3. Following surgery, the patient underwent adjuvant therapy with trastuzumab emtansine for approximately one year due to residual tumour disease, alongside ovarian suppression using gonadotropin-releasing hormone agonists and aromatase inhibitors. Additionally, adjuvant radiotherapy was administered to the right breast. Since November 2022, the patient has undergone adjuvant endocrine therapy, comprising letrozole and Goserelin in conjunction with neratinib for one year, a HER2-directed tyrosine kinase inhibitor. 2.2 Genetic Testing Genetic counselling and germline genetic testing using Next Generation Sequencing (NGS) of the patient were performed in 06/2024 in another clinic, identifying a pathogenic heterozygous variant NM_007294.4:c.1335_1336del, p.(Arg446Serfs*9) in the BRCA1 -Gene. We performed a diagnostic NGS panel analysis covering all known cancer-associated genes (including the most relevant HBOC Core-genes), using genomic DNA extracted from peripheral blood leukocytes to confirm the previously known variant. Panel analysis was performed using Next-Generation-Sequencing via TWIST targeted enrichment following by short read sequencing on a NovaSeq6000 (Illumina) without detecting a mosaic. Variant nomenclature followed HGVS guidelines, with genomic positions referenced to hg38 ( 17 ). Variant classification adhered to ClinGen ENIGMA BRCA1/BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 v1.2 ( 18 ). The deletion of the two nucleotides leads to a frameshift and consequently to a premature stop codon (ACMG criteria applied: PVS1, PM5_STR_PTC), most likely resulting in a missing or disrupted protein product. This variant does not occur in the general population (gnomAD: 0%, v.4.1.0, ACMG criterion applied: PM2_SUP) ( 19 ). It is listed twice in the HGMD database (ID: CD044265) ( 20 ). The variant was assessed as pathogenic 6 times in ClinVar (ID: 54205) ( 21 ). The polygenic risk score (PRS) for breast cancer was 1.6071 (z-score), placing the patient at the 94.598th percentile of the reference distribution; however, this value is still considered within the normal range. The genetic ancestry was calculated as European. The breast cancer PRS was calculated based on 313 breast cancer–associated variants (BCAC313) as defined by Mavaddat et al. ( 22 ). Subsequently, the patient’s biological parents attended our genetics clinic for cascade testing to determine their carrier status for the familial BRCA1 pathogenic variant in 2025. We performed the abovementioned NGS analysis to segregate for the BRCA1 -variant. However genetic testing of the patient’s biological parents did not reveal the familial BRCA1 variant, indicating that the patient had a d e novo variant. To ensure the genetic parentage, we performed a microsatellite analysis. Six out of nine markers were informative for the confirmation of parenthood. 3. Discussion Since 1999, a range of de novo BRCA1 variants has been reported, including small deletions or frameshift variants ( 11 , 15 ), splice-site changes ( 8 , 13 ), whole or partial gene deletions ( 7 , 9 , 10 ), and missense variants ( 13 , 14 , 16 ) (Table 1 ). Of note, mosaicism was reported in two cases ( 12 , 13 ). Most patients presented with early-onset breast cancer, often before the age of 40 and with high-grade, invasive ductal carcinoma ( 7 – 10 , 14 , 16 ). Triple-negative breast cancer (TNBC), was reported in several cases ( 9 , 12 , 16 ). Two patients presented with ovarian cancer ( 11 , 13 ). A striking aspect of de novo variants is the absence of a significant family history in many cases ( 9 , 11 , 13 , 14 ). While some patients reported limited cancer history in relatives (e.g., paternal or maternal cousins with breast cancer), these were often not in direct first-degree relatives ( 9 , 10 , 12 , 13 , 15 , 16 ). It is also important to note that the presence of breast cancer in more distant relatives may reflect the overall high prevalence of breast cancer in the general population (13,2% in Germany), rather than indicating a hereditary cancer syndrome ( 23 ). The presented patient underwent genetic testing despite not meeting the German HBOC criteria that would typically justify genetic diagnostic ( 24 ). She was not diagnosed before the age of 36, did not present with triple-negative breast cancer, and had no notable family history of the disease. The reason for external testing two years after the initial diagnosis remains unclear. In Germany, in cases of de novo variants in breast cancer genes, patients are generally only offered genetic testing once they already developed breast or ovarian cancer, since their family history is often unremarkable and preventive testing in relatives is not typically justified. Without testing, a de novo pathogenic variant would remain undetected, potentially delaying appropriate surveillance and risk reducing surgery (mastectomy and/or salpingo-oophorectomy) for both the patient and her children. Furthermore, the patient’s children are now eligible for genetic testing—an entitlement they would not have had if the pathogenic BRCA1 variant had not been identified in the patient. Broader access to comprehensive sequencing and inclusion in the German Consortium-HBOC surveillance program are essential to ensure that both patients and their families receive appropriate risk assessment, surveillance, and preventive care. With more comprehensive sequencing now available, the true frequency of de novo BRCA1 mutations may be higher than the currently assumed 0,4% ( 17 ). To not oversee patients without positive family history, broadening of inclusion criteria for genetic testing can be discussed. We present another rare case of a de novo BRCA1 variant in a young breast cancer patient. Pathogenic de novo BRCA1 variants, though rare, are clinically significant and may be underdiagnosed due to historical testing limitations and reliance on family history, as well as the lack of parental testing, especially in older patients where parents are often no longer available for analysis. Our case reinforces the need for genetic testing in all breast cancer patients with early onset or aggressive subtypes, regardless of family history. Table 1 De novo variants in BRCA1 , reported in the literature since 1999 and features of the affected individuals Year, Reference De novo Variant (NM_007294.4)* Clinical Features (Age of diagnosis, Tumour identity) Family History, age of diagnosis 1999 ( 7 ) c.3770_3771del, p.(Glu1257fs*9) A, p? bilateral BC; 38, invasive ductal BC, grade 2, ER+; 43, invasive ductal BC grade 3, ER+, PR+ Maternal aunt BC, age 54 2011 ( 9 ) Deletion Ex 1–12* 30, invasive ductal BC, grade 2, TNBC None 2011 ( 10 ) Complete BRCA1 gene deletion* Bilateral BC; 28, invasive ductal carcinoma; 37, medullary carcinoma Paternal cousin BC 42, uncle prostate cancer 2012 ( 11 ) c.3494_3495del, p.(Phe1165Cysfs*2) 52, BC; 53, ovarian cancer None 2013 ( 12 ) Deletion of BRCA1 exon 16 (mosaic)* Bilateral BC; 39, grade 3, TNBC; 47, ductal carcinoma in situ, grade 3, TNBC Paternal cousin BC, age 30 2016 ( 13 ) c.5468-2 A > G, p.? 39, ovarian cancer 2 paternal aunts BC, age 57, 75 2016 ( 13 ) c.2296_2297del, p.(Ser766*) 31, BC None 2016 ( 13 ) Mosaic exons 1–13 deletion* 41, invasive ductal BC 2 sisters BC, age 62, 63; paternal grandmother BC, age 75 2017 ( 14 ) c.5095C > T, p.(Arg1699Trp) 32, invasive ductal BC, ER+, PR+, HER2- None 2023 ( 15 ) c.4065_4068del, p.(Asn1355Lysfs*10) 30, invasive BC, HR+, HER2- Cousin of father BC, age 55 2023 ( 16 ) c.121C > T, p.(His41Tyr) 29, invasive ductal BC, high-grade, TNBC Maternal grandfather prostate cancer, age 85 * All exon-spanning or whole-gene deletions are reported as described in the original publications. Due to the use of non-standardized or custom exon-numbering systems and the absence of unambiguous reference transcripts in several sources, a reliable concordance with exon numbering in NM_007294.4 cannot be ensured. Abbreviations BC Breast cancer BRCA1 Breast Cancer 1 Gene ER Estrogen receptor HBOC Hereditary breast and ovarian cancer HER Human epidermal growth factor NCCN National Comprehensive Cancer Network NGS Next Generation Sequencing PR Progesterone receptor PRS Polygenic Risk Score TNBC Triple negative breast cancer Declarations Ethics approval and consent to participate The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participant. Consent for publication Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article. Availability of data and materials The data that support the findings of this study are available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests Funding The other authors declare that they have no known competing financial interests or personal relation-ships that could have appeared to influence the work re-ported in this paper. Authors' contributions CD: writing—original draft preparation, VS: writing—review and editing, clinical care of the investigated individual and contributed relevant clinical information, BA: writing—review and editing, clinical care of the investigated individual and contributed relevant clinical information, JL: conceptualization, writing—review and editing, JH: writing – review and editing, All authors have read and agreed to the published version of the manuscript Acknowledgements The authors thank the patient and her family for their participation. References Kim J, Harper A, McCormack V, Sung H, Houssami N, Morgan E et al. Global patterns and trends in breast cancer incidence and mortality across 185 countries. Nat Med 2025; 31(4):1154–62. Huang J, Chan PS, Lok V, Chen X, Ding H, Jin Y et al. Global incidence and mortality of breast cancer: a trend analysis. Aging (Albany NY) 2021; 13(4):5748–803. Hu C, Hart SN, Gnanaolivu R, Huang H, Lee KY, Na J et al. A Population-Based Study of Genes Previously Implicated in Breast Cancer. N Engl J Med 2021; 384(5):440–51. Rodriguez-Hernandez A, Martínez-Sáez O, Brasó-Maristany F, Conte B, Gómez R, García-Fructuoso I et al. Prevalence and clinical impact of germline pathogenic variants in breast cancer: a descriptive large single-center study. ESMO Open 2025; 10(4):104543. Nelson HD, Fu R, Goddard K, et al. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: Systematic Review to Update the U.S. Preventive Services Task Force Recommendation [Internet]. [cited 2025 Dec 9]. Available from: URL: https://www.ncbi.nlm.nih.gov/books/NBK179204/table/appa.t2/. Daly MB, Pal T, Berry MP, Buys SS, Dickson P, Domchek SM et al. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021; 19(1):77–102. Tesoriero A, Andersen C, Southey M, Somers G, McKay M, Armes J et al. De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2 mutation. Am J Hum Genet 1999; 65(2):567–9. Edwards E, Yearwood C, Sillibourne J, Baralle D, Eccles D. Identification of a de novo BRCA1 mutation in a woman with early onset bilateral breast cancer. Fam Cancer 2009; 8(4):479–82. Kwong A, Ng EKO, Tang EYH, Wong CLP, Law FBF, Leung CPH et al. A novel de novo BRCA1 mutation in a Chinese woman with early onset breast cancer. Fam Cancer 2011; 10(2):233–7. Garcia-Casado Z, Romero I, Fernandez-Serra A, Rubio L, Llopis F, Garcia A et al. A de novo complete BRCA1 gene deletion identified in a Spanish woman with early bilateral breast cancer. BMC Med Genet 2011; 12:134. Leeneer K de, Coene I, Crombez B, Simkens J, van den Broecke R, Bols A et al. Prevalence of BRCA1/2 mutations in sporadic breast/ovarian cancer patients and identification of a novel de novo BRCA1 mutation in a patient diagnosed with late onset breast and ovarian cancer: implications for genetic testing. Breast Cancer Res Treat 2012; 132(1):87–95. Delon I, Taylor A, Molenda A, Drummond J, Oakhill K, Girling A et al. A germline mosaic BRCA1 exon deletion in a woman with bilateral basal-like breast cancer. Clin Genet 2013; 84(3):297–9. Golmard L, Delnatte C, Laugé A, Moncoutier V, Lefol C, Abidallah K et al. Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations. Oncogene 2016; 35(10):1324–7. Antonucci I, Provenzano M, Sorino L, Rodrigues M, Palka G, Stuppia L. A new case of "de novo" BRCA1 mutation in a patient with early-onset breast cancer. Clin Case Rep 2017; 5(3):238–40. Scherz A, Stoll S, Rothlisberger B, Rabaglio M. A New de novo BRCA1 Mutation in a Young Breast Cancer Patient: A Case Report. Appl Clin Genet 2023; 16:83–7. Gebhart P, Tan Y, Muhr D, Stein C, Singer C. A de Novo BRCA1 Pathogenic Variant in a 29-Year-Old Woman with Triple-Negative Breast Cancer. Breast Care (Basel) 2023; 18(5):412–6. Dunnen JT den, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, McGowan-Jordan J et al. HGVS Recommendations for the Description of Sequence Variants: 2016 Update. Hum Mutat 2016; 37(6):564–9. ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel. ClinGen Criteria Specification Registry (CSpec) [Internet]. Entry GN092. ClinGen / CSpec [cited 2025 Dec 9]. Available from: URL: https://cspec.genome.network/cspec/ui/svi/doc/GN092. Broad Institute. gnomAD. Genome Aggregation Database [Internet]. [cited 2025 Dec 9]. Available from: URL: https://gnomad.broadinstitute.org/. Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical genomics and diagnostic context. Hum Genet. 2020;139(9):1197-1207. Accessed via HGMD Professional (QIAGEN Digital Insights) [Internet]. Entry: CD044265. [cited 2025 Dec 9]. National Center for Biotechnology Information. ClinVar [Internet]. Variation ID 54205. NM_007294.4(BRCA1):c.1335_1336del (p.Arg446fs) [cited 2025 Dec 9]. [cited 2025 Dec 9]. Available from: URL: https://www.ncbi.nlm.nih.gov/clinvar/variation/54205/?oq=NM_007294.4:c.1335_1336del. Mavaddat N, Michailidou K, Dennis J, Lush M, Fachal L, Lee A et al. Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes. Am J Hum Genet 2019; 104(1):21–34. Ronckers C, Spix C, Trübenbach C, Katalinic A, Christ M, Cicero A et al. Krebs in Deutschland für 2019/2020; 2023 [cited 2025 Dec 11]. Available from: URL: https://www.krebsdaten.de/Krebs/DE/Content/Publikationen/Krebs_in_Deutschland/krebs_in_deutschland_node.html. Rhiem K, Bücker-Nott H-J, Hellmich M, Fischer H, Ataseven B, Dittmer-Grabowski C et al. Benchmarking of a checklist for the identification of familial risk for breast and ovarian cancers in a prospective cohort. Breast J 2019; 25(3):455–60. Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterial.docx Cite Share Download PDF Status: Published Journal Publication published 12 Mar, 2026 Read the published version in Hereditary Cancer in Clinical Practice → Version 1 posted Editorial decision: Revision requested 16 Feb, 2026 Reviews received at journal 16 Feb, 2026 Reviews received at journal 13 Feb, 2026 Reviewers agreed at journal 13 Feb, 2026 Reviewers agreed at journal 28 Jan, 2026 Reviewers invited by journal 28 Jan, 2026 Submission checks completed at journal 15 Jan, 2026 First submitted to journal 15 Jan, 2026 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. 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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-8589545","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":581552530,"identity":"1428fe57-8bbd-492a-a2b7-d5724f8478d3","order_by":0,"name":"Carlotta Dencker","email":"data:image/png;base64,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","orcid":"","institution":"University Hospital Leipzig","correspondingAuthor":true,"prefix":"","firstName":"Carlotta","middleName":"","lastName":"Dencker","suffix":""},{"id":581552531,"identity":"65a62144-01eb-42d8-bbbc-86ad5c87a493","order_by":1,"name":"Vincent Strehlow","email":"","orcid":"","institution":"University Hospital Leipzig","correspondingAuthor":false,"prefix":"","firstName":"Vincent","middleName":"","lastName":"Strehlow","suffix":""},{"id":581552532,"identity":"66b166da-9d69-4505-8f02-77a4b390b329","order_by":2,"name":"Bahriye Aktas","email":"","orcid":"","institution":"University Hospital Leipzig","correspondingAuthor":false,"prefix":"","firstName":"Bahriye","middleName":"","lastName":"Aktas","suffix":""},{"id":581552533,"identity":"35145c24-5bea-4944-a97d-4d522f28c7e5","order_by":3,"name":"Johannes Lemke","email":"","orcid":"","institution":"University Hospital Leipzig","correspondingAuthor":false,"prefix":"","firstName":"Johannes","middleName":"","lastName":"Lemke","suffix":""},{"id":581552534,"identity":"d992a422-0696-4743-8617-5a47c538157e","order_by":4,"name":"Julia Hentschel","email":"","orcid":"","institution":"University Hospital Leipzig","correspondingAuthor":false,"prefix":"","firstName":"Julia","middleName":"","lastName":"Hentschel","suffix":""}],"badges":[],"createdAt":"2026-01-13 08:53:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8589545/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8589545/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13053-026-00333-2","type":"published","date":"2026-03-12T15:59:01+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":104739383,"identity":"2feb8945-f0a2-462f-821a-f81bf056f574","added_by":"auto","created_at":"2026-03-16 16:05:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":494647,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8589545/v1/91911112-97bb-4a12-87a5-c88c96dc76c0.pdf"},{"id":101502192,"identity":"37705086-dfaa-47b8-a130-73431cdfcbb5","added_by":"auto","created_at":"2026-01-30 13:46:04","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":84581,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-8589545/v1/d147853d86f98c82973ea3a3.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Case report: A rare BRCA1 de novo variant in a female with breast cancer","fulltext":[{"header":"1. Background","content":"\u003cp\u003eBreast cancer is the most common malignancy among women worldwide, with an incidence of 47 per 100.000 women (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Incidence rates are particularly increasing in Western countries, largely due to lifestyle factors, such as overweight, smoking, alcohol consumption, and hormonal influences (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). However, 5-14.1% of breast cancer cases are attributable to pathogenic genetic variants in common breast cancer genes, with pathogenic variants in the \u003cem\u003eBRCA1\u003c/em\u003e gene being a well-known cause (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Pathogenic \u003cem\u003eBRCA1\u003c/em\u003e variants also increase the risk of ovarian cancer and, in men, prostate cancer and are inherited in an autosomal dominant manner. Consequently, these variants are frequently associated with a notable family history of the disease, and family history remains a central criterion for genetic testing.\u003c/p\u003e \u003cp\u003eAccording to established guidelines (such as the HBOC (Hereditary breast and ovarian cancer) or NCCN (National Comprehensive Cancer Network) criteria (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)), individuals undergo genetic testing if they meet specific clinical or familial risk factors, including early-onset breast cancer, triple-negative phenotype, bilateral disease, or a family history of breast or ovarian cancer. A genetically confirmed pathogenic variant in one of the breast cancer susceptibility genes (e.g. \u003cem\u003eBRCA1\u003c/em\u003e) qualifies patients to participate in intensive early detection programs, which may include enhanced imaging surveillance and consideration of risk-reducing surgery, to facilitate early diagnosis or recurrence detection. Although most \u003cem\u003eBRCA1\u003c/em\u003e variants are inherited, \u003cem\u003ede novo\u003c/em\u003e variants can occur. To date, only twelve cases of \u003cem\u003ede novo BRCA1\u003c/em\u003e variants have been reported in the literature, often identified in young patients with early-onset breast cancer and unremarkable family histories (\u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). In this case report, we describe another instance of a young woman with breast cancer who had no remarkable family history and was found to carry a pathogenic \u003cem\u003ede novo BRCA1\u003c/em\u003e variant.\u003c/p\u003e"},{"header":"2. Case Presentation","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Patients Presentation\u003c/h2\u003e \u003cp\u003eWe present a case study of a 37-year-old female patient who was diagnosed with an invasive carcinoma of the right breast in 2020. The family history was unremarkable with regard to genetic tumour predisposition syndromes, in particular breast and ovarian cancer (see Supplement Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). An initial ultrasound examination identified a tumour measuring 1.1 \u0026times; 0.6 \u0026times; 5.0 cm, a finding that was subsequently confirmed by magnetic resonance imaging. No additional lesions suggestive of metastatic disease were detected on imaging. The patient underwent neoadjuvant systemic therapy consisting of 12 cycles of paclitaxel combined with dual receptor blockade, followed by four cycles of epirubicin and cyclophosphamide chemotherapy. Surgical management entailed breast-conserving surgery (lumpectomy) with a sentinel lymph node biopsy. Histopathological evaluation revealed a tumour with 100% positivity for oestrogen receptor (ER) and progesterone receptor (PR). Human epidermal growth factor receptor 2 (HER2/neu) status was scored as 3\u0026thinsp;+\u0026thinsp;by immunohistochemistry. The Ki-67 proliferation index was quantified at 35%. Tumour staging at diagnosis was clinical T1c N0 M0, with a histological grade of G3. Following surgery, the patient underwent adjuvant therapy with trastuzumab emtansine for approximately one year due to residual tumour disease, alongside ovarian suppression using gonadotropin-releasing hormone agonists and aromatase inhibitors. Additionally, adjuvant radiotherapy was administered to the right breast. Since November 2022, the patient has undergone adjuvant endocrine therapy, comprising letrozole and Goserelin in conjunction with neratinib for one year, a HER2-directed tyrosine kinase inhibitor.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Genetic Testing\u003c/h2\u003e \u003cp\u003eGenetic counselling and germline genetic testing using Next Generation Sequencing (NGS) of the patient were performed in 06/2024 in another clinic, identifying a pathogenic heterozygous variant NM_007294.4:c.1335_1336del, p.(Arg446Serfs*9) in the \u003cem\u003eBRCA1\u003c/em\u003e-Gene. We performed a diagnostic NGS panel analysis covering all known cancer-associated genes (including the most relevant HBOC Core-genes), using genomic DNA extracted from peripheral blood leukocytes to confirm the previously known variant. Panel analysis was performed using Next-Generation-Sequencing via TWIST targeted enrichment following by short read sequencing on a NovaSeq6000 (Illumina) without detecting a mosaic. Variant nomenclature followed HGVS guidelines, with genomic positions referenced to hg38 (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Variant classification adhered to ClinGen ENIGMA BRCA1/BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for \u003cem\u003eBRCA1\u003c/em\u003e v1.2 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe deletion of the two nucleotides leads to a \u003cem\u003eframeshift\u003c/em\u003e and consequently to a premature stop codon (ACMG criteria applied: PVS1, PM5_STR_PTC), most likely resulting in a missing or disrupted protein product. This variant does not occur in the general population (gnomAD: 0%, v.4.1.0, ACMG criterion applied: PM2_SUP) (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). It is listed twice in the HGMD database (ID: CD044265) (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). The variant was assessed as pathogenic 6 times in ClinVar (ID: 54205) (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe polygenic risk score (PRS) for breast cancer was 1.6071 (z-score), placing the patient at the 94.598th percentile of the reference distribution; however, this value is still considered within the normal range. The genetic ancestry was calculated as European. The breast cancer PRS was calculated based on 313 breast cancer\u0026ndash;associated variants (BCAC313) as defined by Mavaddat et al. (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSubsequently, the patient\u0026rsquo;s biological parents attended our genetics clinic for cascade testing to determine their carrier status for the familial \u003cem\u003eBRCA1\u003c/em\u003e pathogenic variant in 2025. We performed the abovementioned NGS analysis to segregate for the \u003cem\u003eBRCA1\u003c/em\u003e-variant. However genetic testing of the patient\u0026rsquo;s biological parents did not reveal the familial \u003cem\u003eBRCA1\u003c/em\u003e variant, indicating that the patient had a d\u003cem\u003ee novo\u003c/em\u003e variant. To ensure the genetic parentage, we performed a microsatellite analysis. Six out of nine markers were informative for the confirmation of parenthood.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eSince 1999, a range of \u003cem\u003ede novo BRCA1\u003c/em\u003e variants has been reported, including small deletions or \u003cem\u003eframeshift\u003c/em\u003e variants (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), splice-site changes (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), whole or partial gene deletions (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), and missense variants (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Of note, mosaicism was reported in two cases (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Most patients presented with early-onset breast cancer, often before the age of 40 and with high-grade, invasive ductal carcinoma (\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Triple-negative breast cancer (TNBC), was reported in several cases (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Two patients presented with ovarian cancer (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). A striking aspect of \u003cem\u003ede novo\u003c/em\u003e variants is the absence of a significant family history in many cases (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). While some patients reported limited cancer history in relatives (e.g., paternal or maternal cousins with breast cancer), these were often not in direct first-degree relatives (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). It is also important to note that the presence of breast cancer in more distant relatives may reflect the overall high prevalence of breast cancer in the general population (13,2% in Germany), rather than indicating a hereditary cancer syndrome (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe presented patient underwent genetic testing despite not meeting the German HBOC criteria that would typically justify genetic diagnostic (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). She was not diagnosed before the age of 36, did not present with triple-negative breast cancer, and had no notable family history of the disease. The reason for external testing two years after the initial diagnosis remains unclear.\u003c/p\u003e \u003cp\u003eIn Germany, in cases of \u003cem\u003ede novo\u003c/em\u003e variants in breast cancer genes, patients are generally only offered genetic testing once they already developed breast or ovarian cancer, since their family history is often unremarkable and preventive testing in relatives is not typically justified. Without testing, a \u003cem\u003ede novo\u003c/em\u003e pathogenic variant would remain undetected, potentially delaying appropriate surveillance and risk reducing surgery (mastectomy and/or salpingo-oophorectomy) for both the patient and her children. Furthermore, the patient\u0026rsquo;s children are now eligible for genetic testing\u0026mdash;an entitlement they would not have had if the pathogenic \u003cem\u003eBRCA1\u003c/em\u003e variant had not been identified in the patient.\u003c/p\u003e \u003cp\u003eBroader access to comprehensive sequencing and inclusion in the German Consortium-HBOC surveillance program are essential to ensure that both patients and their families receive appropriate risk assessment, surveillance, and preventive care. With more comprehensive sequencing now available, the true frequency of \u003cem\u003ede novo BRCA1\u003c/em\u003e mutations may be higher than the currently assumed 0,4% (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). To not oversee patients without positive family history, broadening of inclusion criteria for genetic testing can be discussed.\u003c/p\u003e \u003cp\u003eWe present another rare case of a \u003cem\u003ede novo BRCA1\u003c/em\u003e variant in a young breast cancer patient. Pathogenic \u003cem\u003ede novo BRCA1\u003c/em\u003e variants, though rare, are clinically significant and may be underdiagnosed due to historical testing limitations and reliance on family history, as well as the lack of parental testing, especially in older patients where parents are often no longer available for analysis. Our case reinforces the need for genetic testing in all breast cancer patients with early onset or aggressive subtypes, regardless of family history.\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\u003e\u003cem\u003eDe novo\u003c/em\u003e variants in \u003cem\u003eBRCA1\u003c/em\u003e, reported in the literature since 1999 and features of the affected individuals\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" 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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYear, Reference\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eDe novo\u003c/em\u003e Variant (NM_007294.4)*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eClinical Features (Age of diagnosis, Tumour identity)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFamily History, age of diagnosis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1999 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.3770_3771del, p.(Glu1257fs*9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;40, invasive ductal BC high grade, pathogenic variant in \u003cem\u003eBRCA2-\u003c/em\u003egene (6174delT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFather prostate cancer, age early 50s, pathogenic variant in \u003cem\u003eBRCA2-\u003c/em\u003egene (6174delT)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2009 (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.5332\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A, p?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ebilateral BC; 38, invasive ductal BC, grade 2, ER+; 43, invasive ductal BC grade 3, ER+, PR+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMaternal aunt BC, age 54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2011 (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDeletion Ex 1\u0026ndash;12*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30, invasive ductal BC, grade 2, TNBC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2011 (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eComplete \u003cem\u003eBRCA1\u003c/em\u003e gene deletion*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBilateral BC; 28, invasive ductal carcinoma; 37, medullary carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePaternal cousin BC 42, uncle prostate cancer\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2012 (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.3494_3495del, p.(Phe1165Cysfs*2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52, BC; 53, ovarian cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2013 (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDeletion of \u003cem\u003eBRCA1\u003c/em\u003e exon 16 (mosaic)*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBilateral BC; 39, grade 3, TNBC; 47, ductal carcinoma in situ, grade 3, TNBC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePaternal cousin BC, age 30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2016 (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.5468-2 A\u0026thinsp;\u0026gt;\u0026thinsp;G, p.?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39, ovarian cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 paternal aunts BC, age 57, 75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2016 (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.2296_2297del, p.(Ser766*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31, BC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2016 (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMosaic exons 1\u0026ndash;13 deletion*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41, invasive ductal BC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 sisters BC, age 62, 63; paternal grandmother BC, age 75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2017 (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.5095C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.(Arg1699Trp)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32, invasive ductal BC, ER+, PR+, HER2-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023 (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.4065_4068del, p.(Asn1355Lysfs*10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30, invasive BC, HR+, HER2-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCousin of father BC, age 55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023 (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.121C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.(His41Tyr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29, invasive ductal BC, high-grade, TNBC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMaternal grandfather prostate cancer, age 85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e* All exon-spanning or whole-gene deletions are reported as described in the original publications. Due to the use of non-standardized or custom exon-numbering systems and the absence of unambiguous reference transcripts in several sources, a reliable concordance with exon numbering in NM_007294.4 cannot be ensured.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Breast cancer\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e Breast Cancer 1 Gene\u003c/p\u003e\n\u003cp\u003eER\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Estrogen receptor\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHBOC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Hereditary breast and ovarian cancer\u003c/p\u003e\n\u003cp\u003eHER Human epidermal growth factor\u003c/p\u003e\n\u003cp\u003eNCCN\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;National Comprehensive Cancer Network\u003c/p\u003e\n\u003cp\u003eNGS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Next Generation Sequencing\u003c/p\u003e\n\u003cp\u003ePR\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Progesterone receptor\u003c/p\u003e\n\u003cp\u003ePRS \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Polygenic Risk Score\u003c/p\u003e\n\u003cp\u003eTNBC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Triple negative breast cancer\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe other authors declare that they have no known competing financial interests or personal relation-ships that could have appeared to influence the work re-ported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCD: writing—original draft preparation, VS: writing—review and editing, clinical care of the investigated individual and contributed relevant clinical information, BA: writing—review and editing, clinical care of the investigated individual and contributed relevant clinical information, JL: conceptualization, writing—review and editing, JH: writing – review and editing, All authors have read and agreed to the published version of the manuscript\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the patient and her family for their participation.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKim J, Harper A, McCormack V, Sung H, Houssami N, Morgan E et al. Global patterns and trends in breast cancer incidence and mortality across 185 countries. Nat Med 2025; 31(4):1154\u0026ndash;62.\u003c/li\u003e\n\u003cli\u003eHuang J, Chan PS, Lok V, Chen X, Ding H, Jin Y et al. Global incidence and mortality of breast cancer: a trend analysis. Aging (Albany NY) 2021; 13(4):5748\u0026ndash;803.\u003c/li\u003e\n\u003cli\u003eHu C, Hart SN, Gnanaolivu R, Huang H, Lee KY, Na J et al. A Population-Based Study of Genes Previously Implicated in Breast Cancer. N Engl J Med 2021; 384(5):440\u0026ndash;51.\u003c/li\u003e\n\u003cli\u003eRodriguez-Hernandez A, Mart\u0026iacute;nez-S\u0026aacute;ez O, Bras\u0026oacute;-Maristany F, Conte B, G\u0026oacute;mez R, Garc\u0026iacute;a-Fructuoso I et al. Prevalence and clinical impact of germline pathogenic variants in breast cancer: a descriptive large single-center study. ESMO Open 2025; 10(4):104543.\u003c/li\u003e\n\u003cli\u003eNelson HD, Fu R, Goddard K, et al. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: Systematic Review to Update the U.S. Preventive Services Task Force Recommendation [Internet]. [cited 2025 Dec 9]. Available from: URL: https://www.ncbi.nlm.nih.gov/books/NBK179204/table/appa.t2/.\u003c/li\u003e\n\u003cli\u003eDaly MB, Pal T, Berry MP, Buys SS, Dickson P, Domchek SM et al. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021; 19(1):77\u0026ndash;102.\u003c/li\u003e\n\u003cli\u003eTesoriero A, Andersen C, Southey M, Somers G, McKay M, Armes J et al. De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2 mutation. Am J Hum Genet 1999; 65(2):567\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eEdwards E, Yearwood C, Sillibourne J, Baralle D, Eccles D. Identification of a de novo BRCA1 mutation in a woman with early onset bilateral breast cancer. Fam Cancer 2009; 8(4):479\u0026ndash;82.\u003c/li\u003e\n\u003cli\u003eKwong A, Ng EKO, Tang EYH, Wong CLP, Law FBF, Leung CPH et al. A novel de novo BRCA1 mutation in a Chinese woman with early onset breast cancer. Fam Cancer 2011; 10(2):233\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eGarcia-Casado Z, Romero I, Fernandez-Serra A, Rubio L, Llopis F, Garcia A et al. A de novo complete BRCA1 gene deletion identified in a Spanish woman with early bilateral breast cancer. BMC Med Genet 2011; 12:134.\u003c/li\u003e\n\u003cli\u003eLeeneer K de, Coene I, Crombez B, Simkens J, van den Broecke R, Bols A et al. Prevalence of BRCA1/2 mutations in sporadic breast/ovarian cancer patients and identification of a novel de novo BRCA1 mutation in a patient diagnosed with late onset breast and ovarian cancer: implications for genetic testing. Breast Cancer Res Treat 2012; 132(1):87\u0026ndash;95.\u003c/li\u003e\n\u003cli\u003eDelon I, Taylor A, Molenda A, Drummond J, Oakhill K, Girling A et al. A germline mosaic BRCA1 exon deletion in a woman with bilateral basal-like breast cancer. Clin Genet 2013; 84(3):297\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eGolmard L, Delnatte C, Laug\u0026eacute; A, Moncoutier V, Lefol C, Abidallah K et al. Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations. Oncogene 2016; 35(10):1324\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eAntonucci I, Provenzano M, Sorino L, Rodrigues M, Palka G, Stuppia L. A new case of \u0026quot;de novo\u0026quot; BRCA1 mutation in a patient with early-onset breast cancer. Clin Case Rep 2017; 5(3):238\u0026ndash;40.\u003c/li\u003e\n\u003cli\u003eScherz A, Stoll S, Rothlisberger B, Rabaglio M. A New de novo BRCA1 Mutation in a Young Breast Cancer Patient: A Case Report. Appl Clin Genet 2023; 16:83\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eGebhart P, Tan Y, Muhr D, Stein C, Singer C. A de Novo BRCA1 Pathogenic Variant in a 29-Year-Old Woman with Triple-Negative Breast Cancer. Breast Care (Basel) 2023; 18(5):412\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eDunnen JT den, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, McGowan-Jordan J et al. HGVS Recommendations for the Description of Sequence Variants: 2016 Update. Hum Mutat 2016; 37(6):564\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eClinGen ENIGMA BRCA1 and BRCA2 Expert Panel. ClinGen Criteria Specification Registry (CSpec) [Internet]. Entry GN092. ClinGen / CSpec [cited 2025 Dec 9]. Available from: URL: https://cspec.genome.network/cspec/ui/svi/doc/GN092.\u003c/li\u003e\n\u003cli\u003eBroad Institute. gnomAD. Genome Aggregation Database [Internet]. [cited 2025 Dec 9]. Available from: URL: https://gnomad.broadinstitute.org/.\u003c/li\u003e\n\u003cli\u003eStenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. The Human Gene Mutation Database (HGMD\u0026reg;): optimizing its use in a clinical genomics and diagnostic context. Hum Genet. 2020;139(9):1197-1207. Accessed via HGMD Professional (QIAGEN Digital Insights) [Internet]. Entry: CD044265. [cited 2025 Dec 9].\u003c/li\u003e\n\u003cli\u003eNational Center for Biotechnology Information. ClinVar [Internet]. Variation ID 54205. NM_007294.4(BRCA1):c.1335_1336del (p.Arg446fs) [cited 2025 Dec 9]. [cited 2025 Dec 9]. Available from: URL: https://www.ncbi.nlm.nih.gov/clinvar/variation/54205/?oq=NM_007294.4:c.1335_1336del.\u003c/li\u003e\n\u003cli\u003eMavaddat N, Michailidou K, Dennis J, Lush M, Fachal L, Lee A et al. Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes. Am J Hum Genet 2019; 104(1):21\u0026ndash;34.\u003c/li\u003e\n\u003cli\u003eRonckers C, Spix C, Tr\u0026uuml;benbach C, Katalinic A, Christ M, Cicero A et al. Krebs in Deutschland f\u0026uuml;r 2019/2020; 2023 [cited 2025 Dec 11]. Available from: URL: https://www.krebsdaten.de/Krebs/DE/Content/Publikationen/Krebs_in_Deutschland/krebs_in_deutschland_node.html.\u003c/li\u003e\n\u003cli\u003eRhiem K, B\u0026uuml;cker-Nott H-J, Hellmich M, Fischer H, Ataseven B, Dittmer-Grabowski C et al. Benchmarking of a checklist for the identification of familial risk for breast and ovarian cancers in a prospective cohort. Breast J 2019; 25(3):455\u0026ndash;60.\u003c/li\u003e\n\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":"hereditary-cancer-in-clinical-practice","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"hccp","sideBox":"Learn more about [Hereditary Cancer in Clinical Practice](http://jhoonline.biomedcentral.com)","snPcode":"13053","submissionUrl":"https://submission.nature.com/new-submission/13053/3","title":"Hereditary Cancer in Clinical Practice","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"snapp","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"De novo, breast cancer, BRCA1, HBOC","lastPublishedDoi":"10.21203/rs.3.rs-8589545/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8589545/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u003c/p\u003e\n\u003cp\u003eBreast cancer is the most common cancer among women worldwide. While lifestyle factors contribute to rising incidence, 5–14% of cases result from pathogenic variants in core susceptibility genes such as \u003cem\u003eBRCA1\u003c/em\u003e, which also increases ovarian cancer risk and, in men, prostate cancer risk. \u003cem\u003eBRCA1\u003c/em\u003e variants are typically autosomal dominant, making family history a key criterion for genetic testing under guidelines like HBOC or NCCN. Although usually inherited, \u003cem\u003ede novo BRCA1\u003c/em\u003e mutations occur rarely; only twelve cases have been reported. We present a young woman with breast cancer without a significant family history, and a pathogenic \u003cem\u003ede novo BRCA1\u003c/em\u003e variant.\u003c/p\u003e\n\u003cp\u003eCase Presentation\u003c/p\u003e\n\u003cp\u003eWe report a 37-year-old woman with HER2-positive, ER/PR-positive invasive breast cancer without relevant family history. After imaging-confirmed T1cN0M0 disease, she received neoadjuvant Her2-targeted chemotherapy, breast-conserving surgery, postneoadjuvant trastuzumab emtansine, radiotherapy, and ongoing endocrine therapy.\u003c/p\u003e\n\u003cp\u003eGenetic testing by Next Generation Sequencing revealed a \u003cem\u003eBRCA1 \u003c/em\u003eframeshift variant (NM_007294.4:c.1335_1336del, p.(Arg446Serfs*9)) which was classified as pathogenic per ENIGMA/ACMG guidelines. Absent from population databases and previously reported in cancer cases, it disrupts protein function. Cascade testing showed neither parent carried the variant; microsatellite analysis confirmed parentage, indicating a \u003cem\u003ede novo\u003c/em\u003e mutation.\u003c/p\u003e\n\u003cp\u003eConclusion\u003c/p\u003e\n\u003cp\u003eA rare \u003cem\u003ede novo BRCA1\u003c/em\u003e variant was identified in a young breast cancer patient. Such variants are likely underdiagnosed due to historical testing limitations and reliance on family history. This case highlights the importance of genetic testing and inclusion in hereditary cancer prevention programs, even without a family history.\u003c/p\u003e","manuscriptTitle":"Case report: A rare BRCA1 de novo variant in a female with breast cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-30 13:46:00","doi":"10.21203/rs.3.rs-8589545/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-17T03:54:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-17T01:31:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-13T07:57:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"253008850581674398154927016508623207256","date":"2026-02-13T07:16:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"294283065156662000810651309769386608875","date":"2026-01-28T05:21:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-28T05:10:35+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-15T23:48:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"Hereditary Cancer in Clinical Practice","date":"2026-01-15T07:41:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"hereditary-cancer-in-clinical-practice","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"hccp","sideBox":"Learn more about [Hereditary Cancer in Clinical Practice](http://jhoonline.biomedcentral.com)","snPcode":"13053","submissionUrl":"https://submission.nature.com/new-submission/13053/3","title":"Hereditary Cancer in Clinical Practice","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"snapp","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d022cac1-90ab-4ba8-af0c-74f45df143df","owner":[],"postedDate":"January 30th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-16T16:02:29+00:00","versionOfRecord":{"articleIdentity":"rs-8589545","link":"https://doi.org/10.1186/s13053-026-00333-2","journal":{"identity":"hereditary-cancer-in-clinical-practice","isVorOnly":false,"title":"Hereditary Cancer in Clinical Practice"},"publishedOn":"2026-03-12 15:59:01","publishedOnDateReadable":"March 12th, 2026"},"versionCreatedAt":"2026-01-30 13:46:00","video":"","vorDoi":"10.1186/s13053-026-00333-2","vorDoiUrl":"https://doi.org/10.1186/s13053-026-00333-2","workflowStages":[]},"version":"v1","identity":"rs-8589545","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8589545","identity":"rs-8589545","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}