5’UTR gene regions in germline DNA sequencing panels: lessons from the analysis of breast and ovarian cancer patients of Tatar and Bashkir ethnic origin

5’UTR gene regions in germline DNA sequencing panels: lessons from the analysis of breast and ovarian cancer patients of Tatar and Bashkir ethnic origin | 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 Research Article 5’UTR gene regions in germline DNA sequencing panels: lessons from the analysis of breast and ovarian cancer patients of Tatar and Bashkir ethnic origin Anna P. Sokolenko, Aigul R. Venina, Alexandr A. Romanko, Evgenia V. Belogubova, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6183856/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 May, 2025 Read the published version in Familial Cancer → Version 1 posted 7 You are reading this latest preprint version Abstract Background Tatars and Bashkirs are large and closely related ethnic communities that reside in the territory of the Russian Federation but have managed to preserve their national identity through the course of history. Methods This study included 446 Tatars, 53 Bashkirs, and 26 women of mixed Tatar-Bashkir ethnicity. Germline DNA analysis was performed for 349 breast cancer (BC) patients with clinical features of hereditary disease (family history, or young onset (</= 50 years), or BC bilaterality, or triple-negative receptor status) and 176 subjects with high-grade serous ovarian cancer (HGSOC). Results BRCA1 pathogenic variants (PVs) were detected in 63 women; surprisingly, five Slavic founder alleles accounted for 30 (48%) of the BRCA1 mutations. The genuine Tatar BRCA1 allele, c.5161C>T, was observed in 11 subjects. Among 27 women with BRCA2 PVs, six and five women were carriers of the c.-39-1_-39delGA and c.468dupT variants, respectively. The loss-of-heterozygosity (LOH) test confirmed the pathogenic nature of the c.-39-1_-39delGA [rs758732038] allele, which is located in the 5’UTR of BRCA2 . Analysis of other BC-associated genes revealed single instances of PVs affecting PALB2, TP53, ATM, RAD51 , and RAD51D genes. Conclusion Tatars and Bashkirs, which are ethnically and religiously separated from Russians, carry an unexpectedly high proportion of Slavic BRCA1/2 founder alleles. The identification of recurrent Tatar/Bashkir BRCA2 pathogenic 5’UTR variant c.-39-1_-39delGA calls for a systematic analysis of regulatory regions of cancer-predisposing genes in patients with missing heritability. hereditary breast and ovarian cancer Tatars Bashkirs BRCA1 BRCA2 5’UTR variant Introduction Approximately 5–8% of breast carcinomas (BCs) and 20–40% of high-grade serous ovarian carcinomas (HGSOCs) arise due to inheritance of pathogenic variants (PVs) in tumor-predisposing genes. BRCA1 and BRCA2 are the most established genes for hereditary BC and HGSOC, being the main cause of familial BC/HGSOC clustering in virtually all countries and ethnic groups analyzed [ 1 ]. The role of PALB2 has been convincingly demonstrated in BC development, while its impact on ovarian cancer predisposition remains to be investigated in more detail [ 2 – 7 ]. Germline TP53 alterations are responsible for Li-Fraumeni syndrome, a life-threatening hereditary disorder manifested by soft tissue, brain, lung, breast, and other tumors arising in the first decades of life. Analysis of consecutive series of BC patients revealed that TP53 PVs are a common finding in young-onset BC patients [ 8 , 9 ]. While the above genes are highly penetrant, ATM PVs render only an approximately twofold increase in BC risk. However, ATM heterozygosity is relatively frequent in some populations, thus, its contribution to overall cancer incidence may reach significant estimates [ 10 – 12 ]. Several other BC/HGSOC-associated genes have been discovered in the past, e.g., RAD51C and RAD51D , however, they only account for a minor proportion of BC and HGSOC incidence [ 13 – 15 ]. The spectrum of hereditary diseases varies significantly between different populations and ethnicities, thus reflecting the genetic burden of their founders [ 16 , 17 ]. Significant variation has been reported for the BRCA1/2 genes: for example, BRCA1 PVs are particularly characteristic of Slavic countries, whereas BRCA2 appears to be the major contributor to hereditary BC/HGSOC in Finland or Iceland [ 18 ]. Many ethnic communities are characterized by a predominance of recurrent BRCA1/2 alleles as a result of some degree of genetic isolation. The development of an ethnicity-specific worldwide catalog of BC/HGSOC-predisposing PVs is of high importance, as it may uncover novel gene-disease associations and help to adjust genetic testing to local circumstances. Tatars and Bashkirs, being closely related ethnic groups, are the largest non-Slavic communities residing in the Russian Federation. Their settlements are located mainly nearby the Volga River, although some other regions of the country are also enriched for representatives of these nationalities. The total number of Tatars and Bashkirs approaches approximately 5 and 1.5 million people, respectively. The Republic of Tatarstan, located on the Volga River, has a population of 4 million people, with approximately half of them belonging to Tatar nationality. The Republic of Bashkortostan has about the same number of inhabitants; only a third of them are ethnic Bashkirs while as many as a quarter are Tatars. Many Tatars also reside in other Volga cities (Astrakhan, Nizhniy Novgorod, Samara) as well as in Western Siberia. Although perfectly integrated into the modern lifestyle, Tatars and Bashkirs have managed to preserve their ethnic identity. This is partially attributed to religious traditions, given that the majority of Tatars and Bashkirs follow Islam, while neighboring Slavs are influenced by the Christian Orthodox Church [ 19 ]. This study aimed at the investigation of major BC/HGSOC-predisposing genes in Tatar and Bashkir breast and ovarian cancer patients. Methods Study subjects The study was initiated in 2020. The doctors were invited to recruit patients who had either breast cancer with clinical features of hereditary disease (family history, or young onset (</= 50 years), or BC bilaterality, or triple-negative receptor status) or high-grade serous ovarian cancer. All patients underwent free BRCA1, BRCA2, PALB2, TP53 , and ATM germline testing, irrespective of their ethnic origin. However, only subjects with Tatar or Bashkir self-reported status were considered in this report. Informed consent was obtained from all patients. The study included 446 Tatars, 53 Bashkirs, and 26 patients who reported having a mixed Tatar-Bashkir ethnic background. BC patients (n = 349; mean age: 48.6, age range: 25–78) were represented by 292 Tatars, 41 Bashkirs, and 16 Tatar-Bashkirs. Women with HGSOC (n = 176; mean age: 56.6, age range: 38–70) included 154 Tatars, 12 Bashkirs, and 10 Tatar-Bashkirs. The majority of patients were recruited from cities located nearby the Volga River, although a substantial proportion of study subjects arrived from other regions (Table 1 ). Table 1 Sample collection Region No. of patients (N = 525) Ethnic origin Bashkortostan (Ufa) 196 Tatars (N = 137), Bashkirs (N = 37), Tatar-Bashkirs (N = 22) Tatarstan (Kazan, Almetyevsk, Naberezhnye Chelny) 86 Tatars (N = 85), Tatar-Bashkirs (N = 1) Orenburg 49 Tatars (N = 45), Bashkirs (N = 3), Tatar-Bashkirs (N = 1) Saint-Petersburg 41 Tatars (N = 38), Bashkirs (N = 3) Penza 23 Tatars Astrakhan 21 Tatars Western Siberia 22 Tatars Krasnodar region 21 Tatars (N = 19), Bashkirs (N = 2) Chelyabinsk 13 Tatars (N = 8), Bashkirs (N = 5) Saratov 9 Tatars (N = 8), Tatar-Bashkirs (N = 1) Nizhny Novgorod 8 Tatars (N = 7), Bashkirs (N = 1) Kaliningrad 7 Tatars (N = 5), Bashkirs (N = 1), Tatar-Bashkirs (N = 1) Other regions 29 Tatars (N = 28), Bashkirs (N = 1) A total of 304 patients (213 BCs and 91 OCs) who tested negative for pathogenic or likely pathogenic variants in the BRCA1, BRCA2, ATM, PALB2 , or TP53 genes were subjected to the analysis of additional genes that are assumed to be involved in the predisposition to BC or HGSOC, namely BARD1, RAD51, RAD51B, RAD51C, RAD51D, RAD54L , and PTEN. Next-generation sequencing Analysis of the entire coding regions and 5’- and 3’UTRs of BRCA1 (NM_007294.3), BRCA2 (NM_000059.3), PALB2 (NM_024675.3), ATM (NM_000051.3), TP53 (NM_000546.5), BARD1 (NM_000465.3), RAD54L (NM_003579.3), RAD51B (NM_002877.3), RAD51C (NM_002876.3), RAD51D (NM_002878.3), PTEN (NM_00314.3), and RAD51 (NM_002875.3) genes was performed using next-generation sequencing (NGS). Library preparation was performed using the KAPA HyperPlus Kit (Roche). Dual-index libraries were used to pool up to 96 samples in one enrichment reaction. A custom panel of biotinylated probes covering coding sequences, exon-intron boundaries, and 5’- and 3’-untranslated regions of the mentioned genes was utilized for the enrichment of the DNA libraries. The hybridization step consisted of two rounds and was carried out overnight. Sequencing was performed on either Illumina NextSeq 550 platform with the Mid Output Kit v2.5 or GeneMind GenoLab M platform with FCM flow cell in paired-end mode for 150 cycles in both orientations. The bioinformatic pipeline included FASTQ files generation, quality assessment, and mapping of the obtained sequences to the hg19 genome using the BWA tool. The DepthOfCoverage tool [ https://gatk.broadinstitute.org/hc/en-us/articles/360041851491-DepthOfCoverage-BETA- ] was utilized for the control of the sequencing quality. DNA specimens with at least 99% of target bases covered at least 15 times were considered for analysis. Aligned reads were subjected to single-nucleotide variants and indels calling with the HaplotypeCaller [ https://gatk.broadinstitute.org/hc/en-us/articles/360037225632-HaplotypeCaller ]. Annotation was made with the SnpEff software tool [ http://pcingola.github.io/SnpEff/ ]. Further selection was made based on variant pathogenicity data from the ClinVar database [ https://www.ncbi.nlm.nih.gov/clinvar/ ]. Nonsense, frameshift, and essential splice site variants without corresponding records in the ClinVar database were also considered and checked for presumable pathogenicity using the VarSome tool [ 20 ]. Selected PVs were manually checked in the Golden Helix Genome Browser [ 21 ]. Results BRCA1/2 mutations were identified in 34/176 (19.3%) HGSOC and 55/349 (15.7%) BC patients. One patient carried pathogenic alleles in both BRCA1 and BRCA2 genes; therefore, the total number of PVs approached 90. BRCA1 PVs accounted for 63/90 (70%) BRCA1/2 mutations. The Slavic BRCA1 c.5266dupC (5382insC) allele was the most common BRCA1 variant, being detected in 19/63 (30.2%) BRCA1 carriers. Despite the strict patient selection, there were multiple instances of the presence of other Slavic alleles (c.181T > G [p.Cys61Gly] (n = 4), c.3700_3704delGTAAA (n = 4), c.3756_3759delGTCT (n = 1), and c.4035delA (n = 2)). Altogether, Slavic founder mutations were observed in 30/63 (48%) BRCA1 PV carriers. These estimates are very close to those observed in studies of Russian subjects [ 22 ]. The most frequent non-Slavic BRCA1 PV was c.5161C > T [p.Gln1721Ter], which was detected in 11 patients. This is apparently a genuine Tatar BRCA1 allele, as it was previously described in patients from the city of Kazan (Table 2 ) [ 23 ]. Table 2 List of pathogenic variants observed in Tatar and Bashkir patients Gene Variant dbSNP ID No. of Cases Region/City BRCA1 c.5266dupC rs80357906 19 Bashkortostan (N = 8), Orenburg (N = 2), Saint-Petersburg (N = 2), other (N = 7) BRCA1 c.5161C > T [p.Gln1721Ter] rs878854957 11 Orenburg (N = 5), Bashkortostan (N = 3), other (N = 3) BRCA1 c.181T > G [p.Cys61Gly] rs28897672 4 Bashkortostan (N = 3), Orenburg (N = 1) BRCA1 c.3700_3704delGTAAA rs80357609 4 Saint-Petersburg (N = 3), Saransk (N = 1) BRCA1 c.3143delG rs886040100 2 Bashkortostan (N = 1), Chelyabinsk (N = 1) BRCA1 c.3331_3334delCAAG rs80357701 2 Astrakhan BRCA1 c.3481_3491delGAAGATACTAG rs80357877 2 Tatarstan (N = 1), Saint-Petersburg (N = 1) BRCA1 c.3855dupT - 2 Kaliningrad (N = 1), Tatarstan (N = 1) BRCA1 c.4035delA rs80357711 2 Tatarstan BRCA1 c.5406 + 1G > C [IVS21 + 1G > C] rs80358028 2 Tatarstan BRCA1 c.1015_1016delAA - 1 Astrakhan BRCA1 c.1040delT rs397508828 1 Chelyabinsk BRCA1 c.1308dupT - 1 Moscow BRCA1 c.1523delC rs80357782 1 Tatarstan BRCA1 c.3136delG - 1 Western Siberia BRCA1 c.3756_3759delGTCT rs80357868 1 Bashkortostan BRCA1 c.3779T > G [p.Leu1260Ter] rs886038025 1 Bashkortostan BRCA1 c.4065_4068delTCAA rs80357508 1 Astrakhan BRCA1 c.4675G > A [p.Glu1559Lys] rs80356988 1 Tatarstan BRCA1 c.4986 + 2_3delTG [IVS15 + 2_3delTG] - 1 Tatarstan BRCA1 c.5096G > A [p.Arg1699Gln] rs41293459 1 Tatarstan BRCA1 c.5277 + 2T > G rs2051494815 1 Orenburg BRCA1 c.5284delA rs80357684 1 Tatarstan BRCA2 c.-39-1_-39delGA rs758732038 6 Bashkortostan (N = 3), Orenburg (N = 1), Tatarstan (N = 1), Saratov (N = 1) BRCA2 c.468dupT rs1555280955 5 Bashkortostan (N = 2), other (N = 3) BRCA2 c.2899_2900delCT rs80359361 3 Tatarstan (N = 1), Bashkortostan (N = 1), Orenburg (N = 1) BRCA2 c.7007 + 1G > A [IVS13 + 1G > A] rs397507891 2 Krasnodar (N = 1), Bashkortostan (N = 1) BRCA2 c.8754 + 1G > A [IVS21 + 1G > A] rs397508006 2 Orenburg (N = 1), Saint-Petersburg (N = 1) BRCA2 c.965_966dupAA - 2 Khantia-Mansia (N = 1), Tatarstan (N = 1) BRCA2 c.2808_2811delACAA rs80359351 1 Saint-Petersburg BRCA2 c.2990T > G [p.Leu997Ter] rs397507649 1 Bashkortostan BRCA2 c.3982delA - 1 Penza BRCA2 c.5603_5606delACAG rs397507356 1 Western Siberia BRCA2 c.9253delA rs80359752 1 Western Siberia BRCA2 c.9312delinsCT - 1 Tatarstan BRCA2 c.9382C > T [p.Arg3128Ter] rs80359212 1 Astrakhan ATM c.8147T > C [p.Val2716Ala] rs587782652 1 Bashkortostan ATM c.9170G > C [p.Ter3057Serext*?] rs2091262802 1 Orenburg PALB2 c.221delA - 1 Komi TP53 c.473G > A [p.Arg158His] rs587782144 1 Saratov TP53 c.818G > A [p.Arg273His] rs28934576 1 Saint-Petersburg RAD51D c.270_271dupTA rs753862052 1 Western Siberia RAD51 c.644 + 1G > A - 1 Tatarstan Among the BRCA2 mutations, the most frequent PVs were c.-39-1_-39delGA (n = 6) and c.468dupT (n = 5). The latter variant has already been described in patients of Tatar origin [ 23 ], whereas a deletion in the regulatory region (5’UTR) c.-39-1_-39delGA [rs758732038] was observed in the Volga region for the first time. Five out of six carriers of this regulatory mutation were Tatars and one was Bashkir. This variant was previously reported in Asian patients [ 24 ]. It is classified as a likely pathogenic allele in the ClinVar database. Tumors from two of the six carriers of this PV were available for loss-of-heterozygosity (LOH) analysis, and somatic deletion of the remaining wild-type allele was detected in both cases analyzed. There were no PVs specific for Bashkirs, and all variants found in this ethnic group were also observed in Tatars. A distinct spectrum of mutations was observed in patients from Astrakhan. Germline pathogenic variants were detected in 5/21 (24%) patients analyzed. Despite the small number of cases from Astrakhan, there were two carriers of the BRCA1 c.3331_3334delCAAG allele [rs80357701]. This PV did not occur in patients from other regions included in this study (Table 2 ). There were two carriers of TP53 pathogenic alleles among BC cases (p.Arg158His [rs587782144] and p.Arg273His [rs587782144]). Only one of these patients was characterized by a relatively young age at BC onset (41 years), while the other patient developed the first and second BC disease at 64 and 66 years, respectively. In addition, two BC patients carried ATM (p.Ter3057Serext*? [rs2091262802]; p.Val2716Ala [rs587782652]) PVs, and one BC patient was heterozygous for the PALB2 c.221delA allele. The contribution of BARD1, RAD51, RAD51B, RAD51C, RAD51D, RAD54L , and PTEN PVs was also insignificant, given that only one BC case with RAD51D c.270_271dupTA [rs753862052] and one HGSOC patient with RAD51 c.644 + 1G > A were identified. Discussion Although Tatars and Bashkirs are major and well-defined ethnic groups residing in the Russian Federation, this is the first study that specifically focused on breast-ovarian cancer predisposing alleles within this community. A previous relevant report included 199 patients from the Republic of Tatarstan; however, only 106 of these women self-reported Tatars [ 23 ]. Several findings from our study are of potential interest. It is absolutely surprising that as many as 30/63 (48%) of the BRCA1 mutations detected in ethnic Tatars were Slavic alleles, which is comparable with estimates obtained in Slavic populations [ 18 ]. Furthermore, this observation is not attributed to the success of a single founder, given that as many as five different recurrent Slavic mutations were observed in Tatar patients. These data are compatible with the results of DNA polymorphism studies: indeed, people from Tatar settlements located on the Volga River appear to share some components of their genetic makeup with populations living in Eastern Europe, as well as with Finno-Ugric ethnicities [ 25 , 26 ]. A similar trend has recently been demonstrated in studies of Northern Russians, who were found to be descendants of ethnic Finns but not Slavs [ 17 , 27 ]. Interestingly, Jewish communities, which also shared areas with Slavic peoples in Eastern Europe, adopted only BRCA1 c.5266dupC (5382insC) and no other Slavic BRCA1 alleles [ 28 ]. Our study demonstrated the recurrent character of the BRCA1 c.5161C > T [p.Gln1721Ter] allele, which was previously observed by Brovkina et al. [ 23 ] and appears to be a genuine Tatar mutation. However, its contribution is significantly lower when compared to Slavic PVs, as only 11/63 (17%) of BRCA1 heterozygotes were carriers of this allele. BRCA2 mutations were significantly less frequent than BRCA1 PVs (63/90 (70%) vs. 27/90 (30%), p = 0.00015); however, the contribution of two recurrent BRCA2 variants (c.-39-1_-39delGA and c.468dupT) was comparable to the estimates observed in other genetically homogeneous populations (11/27 (41%)) [ 18 ]. Importantly, our study provides convincing evidence for the pathogenicity of the BRCA2 c.-39-1_-39delGA allele, which was previously classified as a likely pathogenic variant. Only a few known BRCA1/2 5’UTR pathogenic or likely pathogenic alleles have been described in the literature or relevant databases (ClinVar) [ 28 , 29 ]. Perhaps, BRCA2 c.-39-1_-39delGA is the first 5’UTR variant whose contribution to BRCA1/2 -related disease morbidity appears to be significant, at least in some ethnic groups. One may suggest that some BRCA1/2 PVs located in the 5’UTR were neglected in previous studies, which understandably focused on the coding regions of these genes. The same limitation is likely to apply to other cancer-predisposing genes; for example, no 5’UTR PVs have been described for relatively well-studied participants of genome maintenance, such as PALB2, ATM , or TP53. This may be a significant drawback, given that a number of genetic disorders have been linked to PVs affecting the 5’UTR regions of the involved genes [ 30 ]. Many NGS studies of BC and HGSOC currently include cancer predisposing genes other than BRCA1/2 . Although all available datasets demonstrate some contribution of TP53, PALB2 , and RAD51 family members, none of these genes have yet demonstrated an impact comparable to that of BRCA1/2 , despite the ethnic diversity of the populations analyzed [ 12 ]. Taking all available data, it appears that BRCA1/2 PVs are the leading cause of hereditary BC and HGSOC worldwide, while all other relevant genes are responsible only for a minor fraction of cancer heredity. Several conclusions can be drawn from this study. Tatars and Bashkirs, being ethnically and religiously distinct from Russians, carry a surprisingly high proportion of Slavic BRCA1/2 founder alleles. In addition, some genuine Tatar/Bashkir BRCA1/2 PVs were detected in the present study, including the BRCA2 pathogenic 5’UTR variant c.-39-1_-39delGA. Current genetic research and diagnostics are usually confined to coding regions of disease-predisposing genes, while putative regulatory sequences located immediately upstream of the start codons are rarely included in NGS panels and usually not subjected to systematic analysis. Our study underscores the potential significance of the variations observed in the promoter regions of medically relevant genes. Abbreviations BC breast cancer HGSOC high-grade serous ovarian cancer NGS next-generation sequencing OC ovarian cancer PV pathogenic variant Declarations Author contributions: Conceptualization: Evgeny Imyanitov, Anna Sokolenko; data collection and data curation: Alexandr Sultanbayev, Vadim Askarov, Gulnara Mukhamediarova, Elvina Bakaeva; methodology: Anna Sokolenko, Alexandr Romanko; investigation: Aigul Venina, Maria Syomina, Evgenia Belogubova, Tatiana Velyukhova, Elena Preobrazhenskaya, Alexandr Togo; funding acquisition: Evgeny Imyanitov; supervision: Evgeny Imyanitov; writing – original draft: Evgeny Imyanitov, Anna Sokolenko; writing – review &editing: all authors. Funding information: This work was supported by the Russian Science Foundation [grant number 21-75-30015]. Conflict of interest: The authors declare no conflicts of interest. Ethics approval: The study was approved by the institutional review board of the N.N. Petrov National Medicine Research Center of Oncology and conducted in accordance with the Declaration of Helsinki protocol. All patients gave informed consent for the collection and use of their data for a scientific purpose. Consent to participate: Written informed consent was obtained from all patients. Data availability statement: Additional data are available from the corresponding author upon request. References Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, Olah E, Olopade OI, Solano AR, Teo SH et al (2018) Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat 39:593-620. https://doi.org/10.1002/humu.23406 Bogdanova N, Sokolenko AP, Iyevleva AG, Abysheva SN, Blaut M, Bremer M, Christiansen H, Rave-Fränk M, Dörk T, Imyanitov E (2011) PALB2 mutations in German and Russian patients with bilateral breast cancer. Breast Cancer Res Treat 126:545-550. https://doi.org/10.1007/s10549-010-1290-4 Prokofyeva D, Bogdanova N, Bermisheva M, Zinnatullina G, Hillemanns P, Khusnutdinova E, Dörk T (2012) Rare occurrence of PALB2 mutations in ovarian cancer patients from the Volga-Ural region. Clin Genet 82:100-101. https://doi.org/10.1111/j.1399-0004.2011.01824.x Antoniou AC, Casadei S, Heikkinen T, Barrowdale D, Pylkäs K, Roberts J, Lee A, Subramanian D, De Leeneer K, Fostira F et al (2014) Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371:497-506. https://doi.org/10.1056/NEJMoa1400382 Yang X, Leslie G, Doroszuk A, Schneider S, Allen J, Decker B, Dunning AM, Redman J, Scarth J, Plaskocinska I et al (2020) Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families. J Clin Oncol 38:674-685. https://doi.org/10.1200/JCO.19.01907 Preobrazhenskaya EV, Shleykina AU, Gorustovich OA, Martianov AS, Bizin IV, Anisimova EI, Sokolova TN, Chuinyshena SA, Kuligina ES, Togo AV, Belyaev AM, Ivantsov AO, Sokolenko AP, Imyanitov EN (2021) Frequency and molecular characteristics of PALB2-associated cancers in Russian patients. Int J Cancer 148:203-210. https://doi.org/10.1002/ijc.33317 Narayan P, Ahsan MD, Webster EM, Perez L, Levi SR, Harvey B, Wolfe I, Beaumont S, Brewer JT, Siegel D et al (2023) Partner and localizer of BRCA2 (PALB2) pathogenic variants and ovarian cancer: A systematic review and meta-analysis. Gynecol Oncol 177:72-85. https://doi.org/10.1016/j.ygyno.2023.07.017 Mouchawar J, Korch C, Byers T, Pitts TM, Li E, McCredie MR, Giles GG, Hopper JL, Southey MC (2010) Population-based estimate of the contribution of TP53 mutations to subgroups of early-onset breast cancer: Australian Breast Cancer Family Study. Cancer Res 70:4795-4800. https://doi.org/10.1158/0008-5472.CAN-09-0851 Rogoża-Janiszewska E, Malińska K, Górski B, Scott RJ, Cybulski C, Kluźniak W, Lener M, Jakubowska A, Gronwald J, Huzarski T, Lubiński J, Dębniak T (2021) Prevalence of germline TP53 variants among early-onset breast cancer patients from Polish population. Breast Cancer 28:226-235. https://doi.org/10.1007/s12282-020-01151-7 Thompson D, Duedal S, Kirner J, McGuffog L, Last J, Reiman A, Byrd P, Taylor M, Easton DF (2005) Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst 97:813-822. https://doi.org/10.1093/jnci/dji141 Marabelli M, Cheng SC, Parmigiani G (2016) Penetrance of ATM Gene Mutations in Breast Cancer: A Meta-Analysis of Different Measures of Risk. Genet Epidemiol 40:425-431. https://doi.org/10.1002/gepi.21971 Imyanitov EN, Kuligina ES, Sokolenko AP, Suspitsin EN, Yanus GA, Iyevleva AG, Ivantsov AO, Aleksakhina SN (2023) Hereditary cancer syndromes. World J Clin Oncol 14:40-68. https://doi.org/10.5306/wjco.v14.i2.40 Loveday C, Turnbull C, Ruark E, Xicola RM, Ramsay E, Hughes D, Warren-Perry M, Snape K; Breast Cancer Susceptibility Collaboration (UK); Eccles D et al (2012) Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat Genet 44:475-476. https://doi.org/10.1038/ng.2224 Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, Olson JE, Godwin AK, Pankratz VS, Olswold C et al (2015) Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol 33:304-311. https://doi.org/10.1200/JCO.2014.57.1414 Suszynska M, Ratajska M, Kozlowski P (2020) BRIP1, RAD51C, and RAD51D mutations are associated with high susceptibility to ovarian cancer: mutation prevalence and precise risk estimates based on a pooled analysis of ~30,000 cases. J Ovarian Res 13:50. https://doi.org/10.1186/s13048-020-00654-3 Xiao Q, Lauschke VM (2021) The prevalence, genetic complexity and population-specific founder effects of human autosomal recessive disorders. NPJ Genom Med 6:41. https://doi.org/10.1038/s41525-021-00203-x Yanus GA, Suspitsin EN, Imyanitov EN (2024) The Spectrum of Disease-Associated Alleles in Countries with a Predominantly Slavic Population. Int J Mol Sci 25:9335. https://doi.org/10.3390/ijms25179335 Yanus GA, Savonevich EL, Sokolenko AP, Romanko AA, Ni VI, Bakaeva EK, Gorustovich OA, Bizin IV, Imyanitov EN (2023) Founder vs. non-founder BRCA1/2 pathogenic alleles: the analysis of Belarusian breast and ovarian cancer patients and review of other studies on ethnically homogenous populations. Fam Cancer 22:19-30. https://doi.org/10.1007/s10689-022-00296-y Russian Census (2021) https://rosstat.gov.ru/vpn/2020/Tom5_Nacionalnyj_sostav_i_vladenie_yazykami. Assessed 13 January 2025. Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, Massouras A (2019) VarSome: the human genomic variant search engine Bioinformatics 35:1978-1980. https://doi.org/10.1093/bioinformatics/bty897 Golden Helix GenomeBrowse ® visualization tool (Version 2.x) [Software]. Bozeman, MT: Golden Helix, Inc. http://www.goldenhelix.com. Assessed 10 January 2025 Sokolenko AP, Sokolova TN, Ni VI, Preobrazhenskaya EV, Iyevleva AG, Aleksakhina SN, Romanko AA, Bessonov AA, Gorodnova TV, Anisimova EI et al (2020) Frequency and spectrum of founder and non-founder BRCA1 and BRCA2 mutations in a large series of Russian breast cancer and ovarian cancer patients. Breast Cancer Res Treat 184:229-235. https://doi.org/10.1007/s10549-020-05827-8 Brovkina OI, Shigapova L, Chudakova DA, Gordiev MG, Enikeev RF, Druzhkov MO, Khodyrev DS, Shagimardanova EI, Nikitin AG, Gusev OA (2018) The Ethnic-Specific Spectrum of Germline Nucleotide Variants in DNA Damage Response and Repair Genes in Hereditary Breast and Ovarian Cancer Patients of Tatar Descent. Front Oncol 8:421. https://doi.org/10.3389/fonc.2018.00421 Cao WM, Zheng YB, Gao Y, Ding XW, Sun Y, Huang Y, Lou CJ, Pan ZW, Peng G, Wang XJ (2019) Comprehensive mutation detection of BRCA1/2 genes reveals large genomic rearrangements contribute to hereditary breast and ovarian cancer in Chinese women. BMC Cancer 19:551. https://doi.org/10.1186/s12885-019-5765-3 Akhatova FS, Rizvanova FF, Khusnutdinova EK (2013) Y-Chromosome Haplotypes in the Populations of Tatar in Russia. Middle-East Journal of Scientific Research 17: 507-509. Balanovska EV, Agdzhoyan AT, Zhabagin MK, Yusupov YuM, Skhalyakho RA, Dolinina DO, Padyukova AD, Kuznetsova MA, Markina NV, Atramentova LA, Lavryashina MB, Balanovsky OP (2016) The Tatars of Eurasia: peculiarity of Crimean, Volga and Siberian Tatar gene pools. Lomonosov Journal of Anthropology 3:75-85. [In Russian]. Kushniarevich A, Utevska O, Chuhryaeva M, Agdzhoyan A, Dibirova K, Uktveryte I, Möls M, Mulahasanovic L, Pshenichnov A, Frolova S et al (2015) Genetic Heritage of the Balto-Slavic Speaking Populations: A Synthesis of Autosomal, Mitochondrial and Y-Chromosomal Data. PLoS One 10:e0135820. https://doi.org/10.1371/journal.pone.0135820 Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, Maglott DR (2014) ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res 42:D980-D985. https://doi.org/10.1093/nar/gkt1113 Walsh T, Mandell JB, Norquist BM, Casadei S, Gulsuner S, Lee MK, King MC (2017) Genetic Predisposition to Breast Cancer Due to Mutations Other Than BRCA1 and BRCA2 Founder Alleles Among Ashkenazi Jewish Women. JAMA Oncol 3:1647-1653. https://doi.org/10.1001/jamaoncol.2017.1996 Evans DGR, van Veen EM, Byers HJ, Wallace AJ, Ellingford JM, Beaman G, Santoyo-Lopez J, Aitman TJ, Eccles DM, Lalloo FI, Smith MJ, Newman WG (2018) A Dominantly Inherited 5' UTR Variant Causing Methylation-Associated Silencing of BRCA1 as a Cause of Breast and Ovarian Cancer. Am J Hum Genet 103:213-220. https://doi.org/10.1016/j.ajhg.2018.07.002 de Vooght KM, van Wijk R, van Solinge WW (2009) Management of gene promoter mutations in molecular diagnostics. Clin Chem 55:698-708. https://doi.org/10.1373/clinchem.2008.120931 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 26 May, 2025 Read the published version in Familial Cancer → Version 1 posted Editorial decision: Revision requested 04 May, 2025 Reviews received at journal 28 Apr, 2025 Reviewers agreed at journal 03 Apr, 2025 Reviewers invited by journal 19 Mar, 2025 Editor assigned by journal 10 Mar, 2025 Submission checks completed at journal 10 Mar, 2025 First submitted to journal 08 Mar, 2025 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-6183856","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":426564048,"identity":"752c159b-06f8-4c46-8a1d-e4695f7230da","order_by":0,"name":"Anna P. Sokolenko","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIie3PMQrCMBTG8RcC6ZK2a0For9AScBHxKpaAUw7QwUEoxMldqegtukvBqXSuxCM4KC66GR1FUt0c8t9/vPcB2Gz/2xg8AAyQARDnW0JepNYE/0SQhJc05heL3eWWTULiLKr4sikjDwO5UgMJjg3v0VowQhuerkqVSAy4MBFoRdxDMktlIFjllgo9CTaRqBXsfn+S6KTJWo06SdyKfuBKoa9Qxt2ZSjtJosmA1hO9RbBkuVdcYpSjtYGE+rHDLeOh79QsOE/VcDvPKziZ5n8IzX4ENpvNZnvvASCOQhiVS8SpAAAAAElFTkSuQmCC","orcid":"","institution":"N.N. Petrov National Medicine Research Center of Oncology","correspondingAuthor":true,"prefix":"","firstName":"Anna","middleName":"P.","lastName":"Sokolenko","suffix":""},{"id":426564049,"identity":"c714d1ee-6da7-4201-84d9-8b57e3083983","order_by":1,"name":"Aigul R. Venina","email":"","orcid":"","institution":"N.N. Petrov National Medicine Research Center of Oncology","correspondingAuthor":false,"prefix":"","firstName":"Aigul","middleName":"R.","lastName":"Venina","suffix":""},{"id":426564050,"identity":"1c7fd15e-83f9-462e-b7ff-d5ca5b09fafd","order_by":2,"name":"Alexandr A. Romanko","email":"","orcid":"","institution":"N.N. Petrov National Medicine Research Center of Oncology","correspondingAuthor":false,"prefix":"","firstName":"Alexandr","middleName":"A.","lastName":"Romanko","suffix":""},{"id":426564051,"identity":"8b9c69e5-61d7-4a67-afa6-c8f140f6ae8a","order_by":3,"name":"Evgenia V. Belogubova","email":"","orcid":"","institution":"N.N. Petrov National Medicine Research Center of Oncology","correspondingAuthor":false,"prefix":"","firstName":"Evgenia","middleName":"V.","lastName":"Belogubova","suffix":""},{"id":426564052,"identity":"045fafd7-29b5-4bd0-b51e-f985eff92fde","order_by":4,"name":"Alexandr V. Sultanbayev","email":"","orcid":"","institution":"Republican Clinical Oncology Dispensary, Ufa, Bashkortostan","correspondingAuthor":false,"prefix":"","firstName":"Alexandr","middleName":"V.","lastName":"Sultanbayev","suffix":""},{"id":426564053,"identity":"559625a7-cfb5-4115-beca-dd15d8a63d53","order_by":5,"name":"Vadim E. Askarov","email":"","orcid":"","institution":"Republican Clinical Oncology Dispensary, Ufa, Bashkortostan","correspondingAuthor":false,"prefix":"","firstName":"Vadim","middleName":"E.","lastName":"Askarov","suffix":""},{"id":426564054,"identity":"79f8a8c2-bf2e-4f26-a051-833ef9a6833e","order_by":6,"name":"Gulnara K. Mukhamediarova","email":"","orcid":"","institution":"Republican Clinical Oncology Dispensary named after prof. M.Z. Sigal","correspondingAuthor":false,"prefix":"","firstName":"Gulnara","middleName":"K.","lastName":"Mukhamediarova","suffix":""},{"id":426564055,"identity":"3092087f-b6c0-4a33-a745-a6af3d205edb","order_by":7,"name":"Elvina Kh. Bakaeva","email":"","orcid":"","institution":"N.N. Petrov National Medicine Research Center of Oncology","correspondingAuthor":false,"prefix":"","firstName":"Elvina","middleName":"Kh.","lastName":"Bakaeva","suffix":""},{"id":426564056,"identity":"df498fb8-1ffa-4799-9a24-892e54f7e5a7","order_by":8,"name":"Maria V. Syomina","email":"","orcid":"","institution":"N.N. Petrov National Medicine Research Center of Oncology","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"V.","lastName":"Syomina","suffix":""},{"id":426564057,"identity":"e213c03c-cc8b-4132-a224-a203134c8cea","order_by":9,"name":"Tatiana Yu. Velyukhova","email":"","orcid":"","institution":"N.N. Petrov National Medicine Research Center of Oncology","correspondingAuthor":false,"prefix":"","firstName":"Tatiana","middleName":"Yu.","lastName":"Velyukhova","suffix":""},{"id":426564058,"identity":"4f2cb349-2db9-40b8-b6a5-457547a7b840","order_by":10,"name":"Elena V. Preobrazhenskya","email":"","orcid":"","institution":"N.N. Petrov National Medicine Research Center of Oncology","correspondingAuthor":false,"prefix":"","firstName":"Elena","middleName":"V.","lastName":"Preobrazhenskya","suffix":""},{"id":426564059,"identity":"e3fa28ed-3ad8-4280-994c-dd8923daed49","order_by":11,"name":"Alexandr V. Togo","email":"","orcid":"","institution":"N.N. Petrov National Medicine Research Center of Oncology","correspondingAuthor":false,"prefix":"","firstName":"Alexandr","middleName":"V.","lastName":"Togo","suffix":""},{"id":426564060,"identity":"4409074a-44b5-49e9-aa77-7bb21ddd0e17","order_by":12,"name":"Evgeny N. Imyanitov","email":"","orcid":"","institution":"N.N. Petrov National Medicine Research Center of Oncology","correspondingAuthor":false,"prefix":"","firstName":"Evgeny","middleName":"N.","lastName":"Imyanitov","suffix":""}],"badges":[],"createdAt":"2025-03-08 11:38:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6183856/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6183856/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10689-025-00477-5","type":"published","date":"2025-05-26T15:57:53+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":83783070,"identity":"22e6d71b-3ff3-4fea-b4a2-8c23803bcb4b","added_by":"auto","created_at":"2025-06-02 16:10:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":740714,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6183856/v1/a69cf9a6-ca9b-4cfd-a696-8ca7a1d596bd.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"5’UTR gene regions in germline DNA sequencing panels: lessons from the analysis of breast and ovarian cancer patients of Tatar and Bashkir ethnic origin","fulltext":[{"header":"Introduction","content":"\u003cp\u003eApproximately 5\u0026ndash;8% of breast carcinomas (BCs) and 20\u0026ndash;40% of high-grade serous ovarian carcinomas (HGSOCs) arise due to inheritance of pathogenic variants (PVs) in tumor-predisposing genes. \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e are the most established genes for hereditary BC and HGSOC, being the main cause of familial BC/HGSOC clustering in virtually all countries and ethnic groups analyzed [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The role of \u003cem\u003ePALB2\u003c/em\u003e has been convincingly demonstrated in BC development, while its impact on ovarian cancer predisposition remains to be investigated in more detail [\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Germline \u003cem\u003eTP53\u003c/em\u003e alterations are responsible for Li-Fraumeni syndrome, a life-threatening hereditary disorder manifested by soft tissue, brain, lung, breast, and other tumors arising in the first decades of life. Analysis of consecutive series of BC patients revealed that \u003cem\u003eTP53\u003c/em\u003e PVs are a common finding in young-onset BC patients [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. While the above genes are highly penetrant, \u003cem\u003eATM\u003c/em\u003e PVs render only an approximately twofold increase in BC risk. However, \u003cem\u003eATM\u003c/em\u003e heterozygosity is relatively frequent in some populations, thus, its contribution to overall cancer incidence may reach significant estimates [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Several other BC/HGSOC-associated genes have been discovered in the past, e.g., \u003cem\u003eRAD51C\u003c/em\u003e and \u003cem\u003eRAD51D\u003c/em\u003e, however, they only account for a minor proportion of BC and HGSOC incidence [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe spectrum of hereditary diseases varies significantly between different populations and ethnicities, thus reflecting the genetic burden of their founders [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Significant variation has been reported for the \u003cem\u003eBRCA1/2\u003c/em\u003e genes: for example, \u003cem\u003eBRCA1\u003c/em\u003e PVs are particularly characteristic of Slavic countries, whereas \u003cem\u003eBRCA2\u003c/em\u003e appears to be the major contributor to hereditary BC/HGSOC in Finland or Iceland [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Many ethnic communities are characterized by a predominance of recurrent \u003cem\u003eBRCA1/2\u003c/em\u003e alleles as a result of some degree of genetic isolation. The development of an ethnicity-specific worldwide catalog of BC/HGSOC-predisposing PVs is of high importance, as it may uncover novel gene-disease associations and help to adjust genetic testing to local circumstances.\u003c/p\u003e \u003cp\u003eTatars and Bashkirs, being closely related ethnic groups, are the largest non-Slavic communities residing in the Russian Federation. Their settlements are located mainly nearby the Volga River, although some other regions of the country are also enriched for representatives of these nationalities. The total number of Tatars and Bashkirs approaches approximately 5 and 1.5\u0026nbsp;million people, respectively. The Republic of Tatarstan, located on the Volga River, has a population of 4\u0026nbsp;million people, with approximately half of them belonging to Tatar nationality. The Republic of Bashkortostan has about the same number of inhabitants; only a third of them are ethnic Bashkirs while as many as a quarter are Tatars. Many Tatars also reside in other Volga cities (Astrakhan, Nizhniy Novgorod, Samara) as well as in Western Siberia. Although perfectly integrated into the modern lifestyle, Tatars and Bashkirs have managed to preserve their ethnic identity. This is partially attributed to religious traditions, given that the majority of Tatars and Bashkirs follow Islam, while neighboring Slavs are influenced by the Christian Orthodox Church [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This study aimed at the investigation of major BC/HGSOC-predisposing genes in Tatar and Bashkir breast and ovarian cancer patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eStudy subjects\u003c/p\u003e \u003cp\u003eThe study was initiated in 2020. The doctors were invited to recruit patients who had either breast cancer with clinical features of hereditary disease (family history, or young onset (\u0026lt;/= 50 years), or BC bilaterality, or triple-negative receptor status) or high-grade serous ovarian cancer. All patients underwent free \u003cem\u003eBRCA1, BRCA2, PALB2, TP53\u003c/em\u003e, and \u003cem\u003eATM\u003c/em\u003e germline testing, irrespective of their ethnic origin. However, only subjects with Tatar or Bashkir self-reported status were considered in this report. Informed consent was obtained from all patients.\u003c/p\u003e \u003cp\u003eThe study included 446 Tatars, 53 Bashkirs, and 26 patients who reported having a mixed Tatar-Bashkir ethnic background. BC patients (n\u0026thinsp;=\u0026thinsp;349; mean age: 48.6, age range: 25\u0026ndash;78) were represented by 292 Tatars, 41 Bashkirs, and 16 Tatar-Bashkirs. Women with HGSOC (n\u0026thinsp;=\u0026thinsp;176; mean age: 56.6, age range: 38\u0026ndash;70) included 154 Tatars, 12 Bashkirs, and 10 Tatar-Bashkirs. The majority of patients were recruited from cities located nearby the Volga River, although a substantial proportion of study subjects arrived from other regions (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\u003eSample collection\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegion\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo. of patients (N\u0026thinsp;=\u0026thinsp;525)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEthnic origin\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBashkortostan (Ufa)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e196\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTatars (N\u0026thinsp;=\u0026thinsp;137), Bashkirs (N\u0026thinsp;=\u0026thinsp;37), Tatar-Bashkirs (N\u0026thinsp;=\u0026thinsp;22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTatarstan (Kazan, Almetyevsk, Naberezhnye Chelny)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTatars (N\u0026thinsp;=\u0026thinsp;85), Tatar-Bashkirs (N\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOrenburg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTatars (N\u0026thinsp;=\u0026thinsp;45), Bashkirs (N\u0026thinsp;=\u0026thinsp;3), Tatar-Bashkirs (N\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSaint-Petersburg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTatars (N\u0026thinsp;=\u0026thinsp;38), Bashkirs (N\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePenza\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTatars\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAstrakhan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTatars\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWestern Siberia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTatars\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKrasnodar region\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTatars (N\u0026thinsp;=\u0026thinsp;19), Bashkirs (N\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChelyabinsk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTatars (N\u0026thinsp;=\u0026thinsp;8), Bashkirs (N\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSaratov\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTatars (N\u0026thinsp;=\u0026thinsp;8), Tatar-Bashkirs (N\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNizhny Novgorod\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTatars (N\u0026thinsp;=\u0026thinsp;7), Bashkirs (N\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKaliningrad\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTatars (N\u0026thinsp;=\u0026thinsp;5), Bashkirs (N\u0026thinsp;=\u0026thinsp;1), Tatar-Bashkirs (N\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther regions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTatars (N\u0026thinsp;=\u0026thinsp;28), Bashkirs (N\u0026thinsp;=\u0026thinsp;1)\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\u003eA total of 304 patients (213 BCs and 91 OCs) who tested negative for pathogenic or likely pathogenic variants in the \u003cem\u003eBRCA1, BRCA2, ATM, PALB2\u003c/em\u003e, or \u003cem\u003eTP53\u003c/em\u003e genes were subjected to the analysis of additional genes that are assumed to be involved in the predisposition to BC or HGSOC, namely \u003cem\u003eBARD1, RAD51, RAD51B, RAD51C, RAD51D, RAD54L\u003c/em\u003e, and \u003cem\u003ePTEN.\u003c/em\u003e\u003c/p\u003e \u003cp\u003eNext-generation sequencing\u003c/p\u003e \u003cp\u003eAnalysis of the entire coding regions and 5\u0026rsquo;- and 3\u0026rsquo;UTRs of \u003cem\u003eBRCA1\u003c/em\u003e (NM_007294.3), \u003cem\u003eBRCA2\u003c/em\u003e (NM_000059.3), \u003cem\u003ePALB2\u003c/em\u003e (NM_024675.3), \u003cem\u003eATM\u003c/em\u003e (NM_000051.3), \u003cem\u003eTP53\u003c/em\u003e (NM_000546.5), \u003cem\u003eBARD1\u003c/em\u003e (NM_000465.3), \u003cem\u003eRAD54L\u003c/em\u003e (NM_003579.3), \u003cem\u003eRAD51B\u003c/em\u003e (NM_002877.3), \u003cem\u003eRAD51C\u003c/em\u003e (NM_002876.3), \u003cem\u003eRAD51D\u003c/em\u003e (NM_002878.3), \u003cem\u003ePTEN\u003c/em\u003e (NM_00314.3), and \u003cem\u003eRAD51\u003c/em\u003e (NM_002875.3) genes was performed using next-generation sequencing (NGS). Library preparation was performed using the KAPA HyperPlus Kit (Roche). Dual-index libraries were used to pool up to 96 samples in one enrichment reaction. A custom panel of biotinylated probes covering coding sequences, exon-intron boundaries, and 5\u0026rsquo;- and 3\u0026rsquo;-untranslated regions of the mentioned genes was utilized for the enrichment of the DNA libraries. The hybridization step consisted of two rounds and was carried out overnight. Sequencing was performed on either Illumina NextSeq 550 platform with the Mid Output Kit v2.5 or GeneMind GenoLab M platform with FCM flow cell in paired-end mode for 150 cycles in both orientations. The bioinformatic pipeline included FASTQ files generation, quality assessment, and mapping of the obtained sequences to the hg19 genome using the BWA tool. The DepthOfCoverage tool [\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gatk.broadinstitute.org/hc/en-us/articles/360041851491-DepthOfCoverage-BETA-\u003c/span\u003e\u003cspan address=\"https://gatk.broadinstitute.org/hc/en-us/articles/360041851491-DepthOfCoverage-BETA-\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e] was utilized for the control of the sequencing quality. DNA specimens with at least 99% of target bases covered at least 15 times were considered for analysis. Aligned reads were subjected to single-nucleotide variants and indels calling with the HaplotypeCaller [\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gatk.broadinstitute.org/hc/en-us/articles/360037225632-HaplotypeCaller\u003c/span\u003e\u003cspan address=\"https://gatk.broadinstitute.org/hc/en-us/articles/360037225632-HaplotypeCaller\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e]. Annotation was made with the SnpEff software tool [\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://pcingola.github.io/SnpEff/\u003c/span\u003e\u003cspan address=\"http://pcingola.github.io/SnpEff/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e]. Further selection was made based on variant pathogenicity data from the ClinVar database [\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/clinvar/\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/clinvar/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e]. Nonsense, frameshift, and essential splice site variants without corresponding records in the ClinVar database were also considered and checked for presumable pathogenicity using the VarSome tool [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Selected PVs were manually checked in the Golden Helix Genome Browser [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cem\u003eBRCA1/2\u003c/em\u003e mutations were identified in 34/176 (19.3%) HGSOC and 55/349 (15.7%) BC patients. One patient carried pathogenic alleles in both \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e genes; therefore, the total number of PVs approached 90. \u003cem\u003eBRCA1\u003c/em\u003e PVs accounted for 63/90 (70%) \u003cem\u003eBRCA1/2\u003c/em\u003e mutations. The Slavic \u003cem\u003eBRCA1\u003c/em\u003e c.5266dupC (5382insC) allele was the most common \u003cem\u003eBRCA1\u003c/em\u003e variant, being detected in 19/63 (30.2%) \u003cem\u003eBRCA1\u003c/em\u003e carriers. Despite the strict patient selection, there were multiple instances of the presence of other Slavic alleles (c.181T\u0026thinsp;\u0026gt;\u0026thinsp;G [p.Cys61Gly] (n\u0026thinsp;=\u0026thinsp;4), c.3700_3704delGTAAA (n\u0026thinsp;=\u0026thinsp;4), c.3756_3759delGTCT (n\u0026thinsp;=\u0026thinsp;1), and c.4035delA (n\u0026thinsp;=\u0026thinsp;2)). Altogether, Slavic founder mutations were observed in 30/63 (48%) \u003cem\u003eBRCA1\u003c/em\u003e PV carriers. These estimates are very close to those observed in studies of Russian subjects [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The most frequent non-Slavic \u003cem\u003eBRCA1\u003c/em\u003e PV was c.5161C\u0026thinsp;\u0026gt;\u0026thinsp;T [p.Gln1721Ter], which was detected in 11 patients. This is apparently a genuine Tatar \u003cem\u003eBRCA1\u003c/em\u003e allele, as it was previously described in patients from the city of Kazan (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\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\u003eList of pathogenic variants observed in Tatar and Bashkir patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGene\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVariant\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003edbSNP ID\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo. of Cases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRegion/City\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.5266dupC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers80357906\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBashkortostan (N\u0026thinsp;=\u0026thinsp;8), Orenburg (N\u0026thinsp;=\u0026thinsp;2), Saint-Petersburg (N\u0026thinsp;=\u0026thinsp;2), other (N\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.5161C\u0026thinsp;\u0026gt;\u0026thinsp;T [p.Gln1721Ter]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers878854957\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOrenburg (N\u0026thinsp;=\u0026thinsp;5), Bashkortostan (N\u0026thinsp;=\u0026thinsp;3), other (N\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.181T\u0026thinsp;\u0026gt;\u0026thinsp;G [p.Cys61Gly]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers28897672\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBashkortostan (N\u0026thinsp;=\u0026thinsp;3), Orenburg (N\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.3700_3704delGTAAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers80357609\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSaint-Petersburg (N\u0026thinsp;=\u0026thinsp;3), Saransk (N\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.3143delG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers886040100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBashkortostan (N\u0026thinsp;=\u0026thinsp;1), Chelyabinsk (N\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.3331_3334delCAAG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers80357701\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAstrakhan\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.3481_3491delGAAGATACTAG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers80357877\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTatarstan (N\u0026thinsp;=\u0026thinsp;1), Saint-Petersburg (N\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.3855dupT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eKaliningrad (N\u0026thinsp;=\u0026thinsp;1), Tatarstan (N\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.4035delA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers80357711\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTatarstan\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.5406\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;C [IVS21\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;C]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers80358028\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTatarstan\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.1015_1016delAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAstrakhan\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.1040delT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers397508828\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eChelyabinsk\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.1308dupT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMoscow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.1523delC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers80357782\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTatarstan\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.3136delG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eWestern Siberia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.3756_3759delGTCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers80357868\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBashkortostan\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.3779T\u0026thinsp;\u0026gt;\u0026thinsp;G [p.Leu1260Ter]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers886038025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBashkortostan\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.4065_4068delTCAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers80357508\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAstrakhan\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.4675G\u0026thinsp;\u0026gt;\u0026thinsp;A [p.Glu1559Lys]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers80356988\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTatarstan\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.4986\u0026thinsp;+\u0026thinsp;2_3delTG [IVS15\u0026thinsp;+\u0026thinsp;2_3delTG]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTatarstan\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.5096G\u0026thinsp;\u0026gt;\u0026thinsp;A [p.Arg1699Gln]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers41293459\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTatarstan\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.5277\u0026thinsp;+\u0026thinsp;2T\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers2051494815\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOrenburg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.5284delA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers80357684\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTatarstan\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.-39-1_-39delGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers758732038\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBashkortostan (N\u0026thinsp;=\u0026thinsp;3), Orenburg (N\u0026thinsp;=\u0026thinsp;1), Tatarstan (N\u0026thinsp;=\u0026thinsp;1), Saratov (N\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.468dupT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers1555280955\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBashkortostan (N\u0026thinsp;=\u0026thinsp;2), other (N\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.2899_2900delCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers80359361\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTatarstan (N\u0026thinsp;=\u0026thinsp;1), Bashkortostan (N\u0026thinsp;=\u0026thinsp;1), Orenburg (N\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.7007\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A [IVS13\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers397507891\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eKrasnodar (N\u0026thinsp;=\u0026thinsp;1), Bashkortostan (N\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.8754\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A [IVS21\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers397508006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOrenburg (N\u0026thinsp;=\u0026thinsp;1), Saint-Petersburg (N\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.965_966dupAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eKhantia-Mansia (N\u0026thinsp;=\u0026thinsp;1), Tatarstan (N\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.2808_2811delACAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers80359351\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSaint-Petersburg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.2990T\u0026thinsp;\u0026gt;\u0026thinsp;G [p.Leu997Ter]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers397507649\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBashkortostan\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.3982delA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePenza\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.5603_5606delACAG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers397507356\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eWestern Siberia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.9253delA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers80359752\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eWestern Siberia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.9312delinsCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTatarstan\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.9382C\u0026thinsp;\u0026gt;\u0026thinsp;T [p.Arg3128Ter]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers80359212\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAstrakhan\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eATM\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.8147T\u0026thinsp;\u0026gt;\u0026thinsp;C [p.Val2716Ala]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers587782652\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBashkortostan\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eATM\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.9170G\u0026thinsp;\u0026gt;\u0026thinsp;C [p.Ter3057Serext*?]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers2091262802\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOrenburg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePALB2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.221delA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eKomi\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eTP53\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.473G\u0026thinsp;\u0026gt;\u0026thinsp;A [p.Arg158His]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers587782144\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSaratov\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eTP53\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.818G\u0026thinsp;\u0026gt;\u0026thinsp;A [p.Arg273His]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers28934576\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSaint-Petersburg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eRAD51D\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.270_271dupTA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ers753862052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eWestern Siberia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eRAD51\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.644\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTatarstan\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\u003eAmong the \u003cem\u003eBRCA2\u003c/em\u003e mutations, the most frequent PVs were c.-39-1_-39delGA (n\u0026thinsp;=\u0026thinsp;6) and c.468dupT (n\u0026thinsp;=\u0026thinsp;5). The latter variant has already been described in patients of Tatar origin [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], whereas a deletion in the regulatory region (5\u0026rsquo;UTR) c.-39-1_-39delGA [rs758732038] was observed in the Volga region for the first time. Five out of six carriers of this regulatory mutation were Tatars and one was Bashkir. This variant was previously reported in Asian patients [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. It is classified as a likely pathogenic allele in the ClinVar database. Tumors from two of the six carriers of this PV were available for loss-of-heterozygosity (LOH) analysis, and somatic deletion of the remaining wild-type allele was detected in both cases analyzed.\u003c/p\u003e \u003cp\u003eThere were no PVs specific for Bashkirs, and all variants found in this ethnic group were also observed in Tatars. A distinct spectrum of mutations was observed in patients from Astrakhan. Germline pathogenic variants were detected in 5/21 (24%) patients analyzed. Despite the small number of cases from Astrakhan, there were two carriers of the \u003cem\u003eBRCA1\u003c/em\u003e c.3331_3334delCAAG allele [rs80357701]. This PV did not occur in patients from other regions included in this study (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere were two carriers of \u003cem\u003eTP53\u003c/em\u003e pathogenic alleles among BC cases (p.Arg158His [rs587782144] and p.Arg273His [rs587782144]). Only one of these patients was characterized by a relatively young age at BC onset (41 years), while the other patient developed the first and second BC disease at 64 and 66 years, respectively. In addition, two BC patients carried \u003cem\u003eATM\u003c/em\u003e (p.Ter3057Serext*? [rs2091262802]; p.Val2716Ala [rs587782652]) PVs, and one BC patient was heterozygous for the \u003cem\u003ePALB2\u003c/em\u003e c.221delA allele. The contribution of \u003cem\u003eBARD1, RAD51, RAD51B, RAD51C, RAD51D, RAD54L\u003c/em\u003e, and \u003cem\u003ePTEN\u003c/em\u003e PVs was also insignificant, given that only one BC case with \u003cem\u003eRAD51D\u003c/em\u003e c.270_271dupTA [rs753862052] and one HGSOC patient with \u003cem\u003eRAD51\u003c/em\u003e c.644\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A were identified.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAlthough Tatars and Bashkirs are major and well-defined ethnic groups residing in the Russian Federation, this is the first study that specifically focused on breast-ovarian cancer predisposing alleles within this community. A previous relevant report included 199 patients from the Republic of Tatarstan; however, only 106 of these women self-reported Tatars [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Several findings from our study are of potential interest. It is absolutely surprising that as many as 30/63 (48%) of the \u003cem\u003eBRCA1\u003c/em\u003e mutations detected in ethnic Tatars were Slavic alleles, which is comparable with estimates obtained in Slavic populations [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Furthermore, this observation is not attributed to the success of a single founder, given that as many as five different recurrent Slavic mutations were observed in Tatar patients. These data are compatible with the results of DNA polymorphism studies: indeed, people from Tatar settlements located on the Volga River appear to share some components of their genetic makeup with populations living in Eastern Europe, as well as with Finno-Ugric ethnicities [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. A similar trend has recently been demonstrated in studies of Northern Russians, who were found to be descendants of ethnic Finns but not Slavs [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Interestingly, Jewish communities, which also shared areas with Slavic peoples in Eastern Europe, adopted only \u003cem\u003eBRCA1\u003c/em\u003e c.5266dupC (5382insC) and no other Slavic \u003cem\u003eBRCA1\u003c/em\u003e alleles [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur study demonstrated the recurrent character of the \u003cem\u003eBRCA1\u003c/em\u003e c.5161C\u0026thinsp;\u0026gt;\u0026thinsp;T [p.Gln1721Ter] allele, which was previously observed by Brovkina et al. [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] and appears to be a genuine Tatar mutation. However, its contribution is significantly lower when compared to Slavic PVs, as only 11/63 (17%) of \u003cem\u003eBRCA1\u003c/em\u003e heterozygotes were carriers of this allele.\u003c/p\u003e \u003cp\u003e \u003cem\u003eBRCA2\u003c/em\u003e mutations were significantly less frequent than \u003cem\u003eBRCA1\u003c/em\u003e PVs (63/90 (70%) vs. 27/90 (30%), p\u0026thinsp;=\u0026thinsp;0.00015); however, the contribution of two recurrent \u003cem\u003eBRCA2\u003c/em\u003e variants (c.-39-1_-39delGA and c.468dupT) was comparable to the estimates observed in other genetically homogeneous populations (11/27 (41%)) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Importantly, our study provides convincing evidence for the pathogenicity of the \u003cem\u003eBRCA2\u003c/em\u003e c.-39-1_-39delGA allele, which was previously classified as a likely pathogenic variant. Only a few known \u003cem\u003eBRCA1/2\u003c/em\u003e 5\u0026rsquo;UTR pathogenic or likely pathogenic alleles have been described in the literature or relevant databases (ClinVar) [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Perhaps, \u003cem\u003eBRCA2\u003c/em\u003e c.-39-1_-39delGA is the first 5\u0026rsquo;UTR variant whose contribution to \u003cem\u003eBRCA1/2\u003c/em\u003e-related disease morbidity appears to be significant, at least in some ethnic groups. One may suggest that some \u003cem\u003eBRCA1/2\u003c/em\u003e PVs located in the 5\u0026rsquo;UTR were neglected in previous studies, which understandably focused on the coding regions of these genes. The same limitation is likely to apply to other cancer-predisposing genes; for example, no 5\u0026rsquo;UTR PVs have been described for relatively well-studied participants of genome maintenance, such as \u003cem\u003ePALB2, ATM\u003c/em\u003e, or \u003cem\u003eTP53.\u003c/em\u003e This may be a significant drawback, given that a number of genetic disorders have been linked to PVs affecting the 5\u0026rsquo;UTR regions of the involved genes [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMany NGS studies of BC and HGSOC currently include cancer predisposing genes other than \u003cem\u003eBRCA1/2\u003c/em\u003e. Although all available datasets demonstrate some contribution of \u003cem\u003eTP53, PALB2\u003c/em\u003e, and \u003cem\u003eRAD51\u003c/em\u003e family members, none of these genes have yet demonstrated an impact comparable to that of \u003cem\u003eBRCA1/2\u003c/em\u003e, despite the ethnic diversity of the populations analyzed [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Taking all available data, it appears that \u003cem\u003eBRCA1/2\u003c/em\u003e PVs are the leading cause of hereditary BC and HGSOC worldwide, while all other relevant genes are responsible only for a minor fraction of cancer heredity.\u003c/p\u003e \u003cp\u003eSeveral conclusions can be drawn from this study. Tatars and Bashkirs, being ethnically and religiously distinct from Russians, carry a surprisingly high proportion of Slavic \u003cem\u003eBRCA1/2\u003c/em\u003e founder alleles. In addition, some genuine Tatar/Bashkir \u003cem\u003eBRCA1/2\u003c/em\u003e PVs were detected in the present study, including the \u003cem\u003eBRCA2\u003c/em\u003e pathogenic 5\u0026rsquo;UTR variant c.-39-1_-39delGA. Current genetic research and diagnostics are usually confined to coding regions of disease-predisposing genes, while putative regulatory sequences located immediately upstream of the start codons are rarely included in NGS panels and usually not subjected to systematic analysis. Our study underscores the potential significance of the variations observed in the promoter regions of medically relevant genes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eBC\u0026nbsp;\u003c/strong\u003ebreast cancer\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHGSOC\u0026nbsp;\u003c/strong\u003ehigh-grade serous ovarian cancer\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNGS\u0026nbsp;\u003c/strong\u003enext-generation sequencing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOC\u0026nbsp;\u003c/strong\u003eovarian cancer\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePV\u0026nbsp;\u003c/strong\u003epathogenic variant\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: Evgeny Imyanitov, Anna Sokolenko; data collection and data curation: Alexandr Sultanbayev, Vadim Askarov, Gulnara Mukhamediarova, Elvina Bakaeva; methodology: Anna Sokolenko, Alexandr Romanko; investigation: Aigul Venina, Maria Syomina, Evgenia Belogubova, Tatiana Velyukhova, Elena Preobrazhenskaya, Alexandr Togo; funding acquisition: Evgeny Imyanitov; supervision: Evgeny Imyanitov; writing \u0026ndash; original draft: Evgeny Imyanitov, Anna Sokolenko; writing \u0026ndash; review \u0026amp;editing: all authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding information:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Russian Science Foundation [grant number 21-75-30015].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the institutional review board of the N.N. Petrov National Medicine Research Center of Oncology and conducted in accordance with the Declaration of Helsinki protocol. All patients gave informed consent for the collection and use of their data for a scientific purpose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdditional data are available from the corresponding author upon request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, Olah E, Olopade OI, Solano AR, Teo SH et al (2018) Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat 39:593-620. https://doi.org/10.1002/humu.23406 \u003c/li\u003e\n\u003cli\u003eBogdanova N, Sokolenko AP, Iyevleva AG, Abysheva SN, Blaut M, Bremer M, Christiansen H, Rave-Fr\u0026auml;nk M, D\u0026ouml;rk T, Imyanitov E (2011) PALB2 mutations in German and Russian patients with bilateral breast cancer. Breast Cancer Res Treat 126:545-550. https://doi.org/10.1007/s10549-010-1290-4 \u003c/li\u003e\n\u003cli\u003eProkofyeva D, Bogdanova N, Bermisheva M, Zinnatullina G, Hillemanns P, Khusnutdinova E, D\u0026ouml;rk T (2012) Rare occurrence of PALB2 mutations in ovarian cancer patients from the Volga-Ural region. Clin Genet 82:100-101. https://doi.org/10.1111/j.1399-0004.2011.01824.x \u003c/li\u003e\n\u003cli\u003eAntoniou AC, Casadei S, Heikkinen T, Barrowdale D, Pylk\u0026auml;s K, Roberts J, Lee A, Subramanian D, De Leeneer K, Fostira F et al (2014) Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371:497-506. https://doi.org/10.1056/NEJMoa1400382 \u003c/li\u003e\n\u003cli\u003eYang X, Leslie G, Doroszuk A, Schneider S, Allen J, Decker B, Dunning AM, Redman J, Scarth J, Plaskocinska I et al (2020) Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families. J Clin Oncol 38:674-685. https://doi.org/10.1200/JCO.19.01907 \u003c/li\u003e\n\u003cli\u003ePreobrazhenskaya EV, Shleykina AU, Gorustovich OA, Martianov AS, Bizin IV, Anisimova EI, Sokolova TN, Chuinyshena SA, Kuligina ES, Togo AV, Belyaev AM, Ivantsov AO, Sokolenko AP, Imyanitov EN (2021) Frequency and molecular characteristics of PALB2-associated cancers in Russian patients. Int J Cancer 148:203-210. https://doi.org/10.1002/ijc.33317 \u003c/li\u003e\n\u003cli\u003eNarayan P, Ahsan MD, Webster EM, Perez L, Levi SR, Harvey B, Wolfe I, Beaumont S, Brewer JT, Siegel D et al (2023) Partner and localizer of BRCA2 (PALB2) pathogenic variants and ovarian cancer: A systematic review and meta-analysis. Gynecol Oncol 177:72-85. https://doi.org/10.1016/j.ygyno.2023.07.017 \u003c/li\u003e\n\u003cli\u003eMouchawar J, Korch C, Byers T, Pitts TM, Li E, McCredie MR, Giles GG, Hopper JL, Southey MC (2010) Population-based estimate of the contribution of TP53 mutations to subgroups of early-onset breast cancer: Australian Breast Cancer Family Study. Cancer Res 70:4795-4800. https://doi.org/10.1158/0008-5472.CAN-09-0851 \u003c/li\u003e\n\u003cli\u003eRogoża-Janiszewska E, Malińska K, G\u0026oacute;rski B, Scott RJ, Cybulski C, Kluźniak W, Lener M, Jakubowska A, Gronwald J, Huzarski T, Lubiński J, Dębniak T (2021) Prevalence of germline TP53 variants among early-onset breast cancer patients from Polish population. Breast Cancer 28:226-235. https://doi.org/10.1007/s12282-020-01151-7 \u003c/li\u003e\n\u003cli\u003eThompson D, Duedal S, Kirner J, McGuffog L, Last J, Reiman A, Byrd P, Taylor M, Easton DF (2005) Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst 97:813-822. https://doi.org/10.1093/jnci/dji141 \u003c/li\u003e\n\u003cli\u003eMarabelli M, Cheng SC, Parmigiani G (2016) Penetrance of ATM Gene Mutations in Breast Cancer: A Meta-Analysis of Different Measures of Risk. Genet Epidemiol 40:425-431. https://doi.org/10.1002/gepi.21971 \u003c/li\u003e\n\u003cli\u003eImyanitov EN, Kuligina ES, Sokolenko AP, Suspitsin EN, Yanus GA, Iyevleva AG, Ivantsov AO, Aleksakhina SN (2023) Hereditary cancer syndromes. World J Clin Oncol 14:40-68. https://doi.org/10.5306/wjco.v14.i2.40 \u003c/li\u003e\n\u003cli\u003eLoveday C, Turnbull C, Ruark E, Xicola RM, Ramsay E, Hughes D, Warren-Perry M, Snape K; Breast Cancer Susceptibility Collaboration (UK); Eccles D et al (2012) Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat Genet 44:475-476. https://doi.org/10.1038/ng.2224 \u003c/li\u003e\n\u003cli\u003eCouch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, Olson JE, Godwin AK, Pankratz VS, Olswold C et al (2015) Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol 33:304-311. https://doi.org/10.1200/JCO.2014.57.1414 \u003c/li\u003e\n\u003cli\u003eSuszynska M, Ratajska M, Kozlowski P (2020) BRIP1, RAD51C, and RAD51D mutations are associated with high susceptibility to ovarian cancer: mutation prevalence and precise risk estimates based on a pooled analysis of ~30,000 cases. J Ovarian Res 13:50. https://doi.org/10.1186/s13048-020-00654-3 \u003c/li\u003e\n\u003cli\u003eXiao Q, Lauschke VM (2021) The prevalence, genetic complexity and population-specific founder effects of human autosomal recessive disorders. NPJ Genom Med 6:41. https://doi.org/10.1038/s41525-021-00203-x \u003c/li\u003e\n\u003cli\u003eYanus GA, Suspitsin EN, Imyanitov EN (2024) The Spectrum of Disease-Associated Alleles in Countries with a Predominantly Slavic Population. Int J Mol Sci 25:9335. https://doi.org/10.3390/ijms25179335 \u003c/li\u003e\n\u003cli\u003eYanus GA, Savonevich EL, Sokolenko AP, Romanko AA, Ni VI, Bakaeva EK, Gorustovich OA, Bizin IV, Imyanitov EN (2023) Founder vs. non-founder BRCA1/2 pathogenic alleles: the analysis of Belarusian breast and ovarian cancer patients and review of other studies on ethnically homogenous populations. Fam Cancer 22:19-30. https://doi.org/10.1007/s10689-022-00296-y \u003c/li\u003e\n\u003cli\u003eRussian Census (2021) https://rosstat.gov.ru/vpn/2020/Tom5_Nacionalnyj_sostav_i_vladenie_yazykami. Assessed 13 January 2025.\u003c/li\u003e\n\u003cli\u003eKopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, Massouras A (2019) VarSome: the human genomic variant search engine Bioinformatics 35:1978-1980. https://doi.org/10.1093/bioinformatics/bty897 \u003c/li\u003e\n\u003cli\u003eGolden Helix GenomeBrowse \u0026reg; visualization tool (Version 2.x) [Software]. Bozeman, MT: Golden Helix, Inc. http://www.goldenhelix.com. Assessed 10 January 2025 \u003c/li\u003e\n\u003cli\u003eSokolenko AP, Sokolova TN, Ni VI, Preobrazhenskaya EV, Iyevleva AG, Aleksakhina SN, Romanko AA, Bessonov AA, Gorodnova TV, Anisimova EI et al (2020) Frequency and spectrum of founder and non-founder BRCA1 and BRCA2 mutations in a large series of Russian breast cancer and ovarian cancer patients. Breast Cancer Res Treat 184:229-235. https://doi.org/10.1007/s10549-020-05827-8 \u003c/li\u003e\n\u003cli\u003eBrovkina OI, Shigapova L, Chudakova DA, Gordiev MG, Enikeev RF, Druzhkov MO, Khodyrev DS, Shagimardanova EI, Nikitin AG, Gusev OA (2018) The Ethnic-Specific Spectrum of Germline Nucleotide Variants in DNA Damage Response and Repair Genes in Hereditary Breast and Ovarian Cancer Patients of Tatar Descent. Front Oncol 8:421. https://doi.org/10.3389/fonc.2018.00421 \u003c/li\u003e\n\u003cli\u003eCao WM, Zheng YB, Gao Y, Ding XW, Sun Y, Huang Y, Lou CJ, Pan ZW, Peng G, Wang XJ (2019) Comprehensive mutation detection of BRCA1/2 genes reveals large genomic rearrangements contribute to hereditary breast and ovarian cancer in Chinese women. BMC Cancer 19:551. https://doi.org/10.1186/s12885-019-5765-3 \u003c/li\u003e\n\u003cli\u003eAkhatova FS, Rizvanova FF, Khusnutdinova EK (2013) Y-Chromosome Haplotypes in the Populations of Tatar in Russia. Middle-East Journal of Scientific Research 17: 507-509. \u003c/li\u003e\n\u003cli\u003eBalanovska EV, Agdzhoyan AT, Zhabagin MK, Yusupov YuM, Skhalyakho RA, Dolinina DO, Padyukova AD, Kuznetsova MA, Markina NV, Atramentova LA, Lavryashina MB, Balanovsky OP (2016) The Tatars of Eurasia: peculiarity of Crimean, Volga and Siberian Tatar gene pools. Lomonosov Journal of Anthropology 3:75-85. [In Russian].\u003c/li\u003e\n\u003cli\u003eKushniarevich A, Utevska O, Chuhryaeva M, Agdzhoyan A, Dibirova K, Uktveryte I, M\u0026ouml;ls M, Mulahasanovic L, Pshenichnov A, Frolova S et al (2015) Genetic Heritage of the Balto-Slavic Speaking Populations: A Synthesis of Autosomal, Mitochondrial and Y-Chromosomal Data. PLoS One 10:e0135820. https://doi.org/10.1371/journal.pone.0135820 \u003c/li\u003e\n\u003cli\u003eLandrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, Maglott DR (2014) ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res 42:D980-D985. https://doi.org/10.1093/nar/gkt1113 \u003c/li\u003e\n\u003cli\u003eWalsh T, Mandell JB, Norquist BM, Casadei S, Gulsuner S, Lee MK, King MC (2017) Genetic Predisposition to Breast Cancer Due to Mutations Other Than BRCA1 and BRCA2 Founder Alleles Among Ashkenazi Jewish Women. JAMA Oncol 3:1647-1653. https://doi.org/10.1001/jamaoncol.2017.1996 \u003c/li\u003e\n\u003cli\u003eEvans DGR, van Veen EM, Byers HJ, Wallace AJ, Ellingford JM, Beaman G, Santoyo-Lopez J, Aitman TJ, Eccles DM, Lalloo FI, Smith MJ, Newman WG (2018) A Dominantly Inherited 5\u0026apos; UTR Variant Causing Methylation-Associated Silencing of BRCA1 as a Cause of Breast and Ovarian Cancer. Am J Hum Genet 103:213-220. https://doi.org/10.1016/j.ajhg.2018.07.002 \u003c/li\u003e\n\u003cli\u003ede Vooght KM, van Wijk R, van Solinge WW (2009) Management of gene promoter mutations in molecular diagnostics. Clin Chem 55:698-708. https://doi.org/10.1373/clinchem.2008.120931 \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":"familial-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"fame","sideBox":"Learn more about [Familial Cancer](http://link.springer.com/journal/10689)","snPcode":"10689","submissionUrl":"https://submission.nature.com/new-submission/10689/3","title":"Familial Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"hereditary breast and ovarian cancer, Tatars, Bashkirs, BRCA1, BRCA2, 5’UTR variant","lastPublishedDoi":"10.21203/rs.3.rs-6183856/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6183856/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTatars and Bashkirs are large and closely related ethnic communities that reside in the territory of the Russian Federation but have managed to preserve their national identity through the course of history.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study included 446 Tatars, 53 Bashkirs, and 26 women of mixed Tatar-Bashkir ethnicity. Germline DNA analysis was performed for 349 breast cancer (BC) patients with clinical features of hereditary disease (family history, or young onset (\u0026lt;/= 50 years), or BC bilaterality, or triple-negative receptor status) and 176 subjects with high-grade serous ovarian cancer (HGSOC).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e pathogenic variants (PVs) were detected in 63 women; surprisingly, five Slavic founder alleles accounted for 30 (48%) of the \u003cem\u003eBRCA1\u003c/em\u003e mutations. The genuine Tatar \u003cem\u003eBRCA1\u003c/em\u003e allele, c.5161C\u0026gt;T, was observed in 11 subjects. Among 27 women with \u003cem\u003eBRCA2\u003c/em\u003e PVs, six and five women were carriers of the c.-39-1_-39delGA and c.468dupT variants, respectively. The loss-of-heterozygosity (LOH) test confirmed the pathogenic nature of the c.-39-1_-39delGA [rs758732038] allele, which is located in the 5’UTR of \u003cem\u003eBRCA2\u003c/em\u003e.\u003cstrong\u003e \u003c/strong\u003eAnalysis of other BC-associated genes revealed single instances of PVs affecting \u003cem\u003ePALB2, TP53, ATM, RAD51\u003c/em\u003e, and \u003cem\u003eRAD51D \u003c/em\u003egenes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTatars and Bashkirs, which are ethnically and religiously separated from Russians, carry an unexpectedly high proportion of Slavic \u003cem\u003eBRCA1/2\u003c/em\u003e founder alleles. The identification of recurrent Tatar/Bashkir \u003cem\u003eBRCA2\u003c/em\u003e pathogenic 5’UTR variant c.-39-1_-39delGA calls for a systematic analysis of regulatory regions of cancer-predisposing genes in patients with missing heritability.\u003c/p\u003e","manuscriptTitle":"5’UTR gene regions in germline DNA sequencing panels: lessons from the analysis of breast and ovarian cancer patients of Tatar and Bashkir ethnic origin","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-12 06:05:21","doi":"10.21203/rs.3.rs-6183856/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-04T16:37:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-28T08:55:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"175065923952618370258849883203703682746","date":"2025-04-03T14:13:03+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-19T06:51:06+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-10T09:25:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-10T09:20:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"Familial Cancer","date":"2025-03-08T11:24:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"familial-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"fame","sideBox":"Learn more about [Familial Cancer](http://link.springer.com/journal/10689)","snPcode":"10689","submissionUrl":"https://submission.nature.com/new-submission/10689/3","title":"Familial Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"82a0ccd4-4561-4cdc-9048-27c1a44afb3f","owner":[],"postedDate":"March 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-06-02T16:06:31+00:00","versionOfRecord":{"articleIdentity":"rs-6183856","link":"https://doi.org/10.1007/s10689-025-00477-5","journal":{"identity":"familial-cancer","isVorOnly":false,"title":"Familial Cancer"},"publishedOn":"2025-05-26 15:57:53","publishedOnDateReadable":"May 26th, 2025"},"versionCreatedAt":"2025-03-12 06:05:21","video":"","vorDoi":"10.1007/s10689-025-00477-5","vorDoiUrl":"https://doi.org/10.1007/s10689-025-00477-5","workflowStages":[]},"version":"v1","identity":"rs-6183856","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6183856","identity":"rs-6183856","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}