{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T20:05:42Z","timestamp":1790193942787,"version":"4.1.0"},"reference-count":40,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T00:00:00Z","timestamp":1781308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Pathogenic BRCA1 and BRCA2 mutations confer a homologous recombination deficiency that underlies PARP inhibitor sensitivity. While BRCA1 mutation carriers more frequently develop triple-negative breast cancer (TNBC) and BRCA2 carriers hormone receptor-positive (HR+) disease, whether the specific protein domain harboring a pathogenic somatic mutation differs systematically between breast cancer subtypes remains uncertain. Apparent domain enrichment in earlier unfiltered analyses may be confounded by missense variants of uncertain significance (VUSs), which lack clinical actionability. Methods: We assembled three independent breast cancer cohorts via cBioPortal: TCGA-BRCA (brca_tcga_pub2015), METABRIC (brca_metabric), and MSK-CHORD (msk_chord_2024). All somatic BRCA1\/2 mutations were mapped to UniProt-annotated functional domains and to Rebbeck-defined breast\/ovarian cancer cluster regions (BCCR\/OCCR). Per ENIGMA\/ACMG guidance, pathogenic mutations (nonsense, frameshift, and canonical splice site) were analyzed inferentially, while missense and in-frame variants\u2014predominantly VUSs\u2014were only reported descriptively. Fisher\u2019s exact tests with Benjamini\u2013Hochberg FDR correction were applied across domain \u00d7 subtype contingencies. Cohort heterogeneity was assessed via Cochran\u2019s Q and I2 statistics; pooled effect estimates were computed using inverse-variance fixed-effects meta-analysis. Results: A total of 394 somatic BRCA1\/2 mutations were identified across the three cohorts (BRCA1 n = 166; BRCA2 n = 228), of which 147 (37.3%) met pathogenic criteria. Among 131 pathogenic mutations in HR+\/HER2\u2212 or TNBC subtypes, 84 (64.1%) occurred in HR+\/HER2\u2212 disease and 47 (35.9%) in TNBC. Domain-level distributions did not differ significantly between subtypes for any BRCA1 domain (BRCT: TNBC 20.0% vs. HR+ 18.8%, OR = 1.08, 95% CI 0.31\u20133.78, and FDR-adjusted p = 1.00) or BRCA2 domain (DBD: TNBC 17.6% vs. HR+ 30.8%, OR = 0.48, and FDR-adjusted p = 1.00). Cluster-region analyses (nine Rebbeck BCCR\/OCCRs) similarly showed no significant enrichment. Post hoc power analysis indicated that the study could only reliably detect large effects (OR \u2265 ~3.0 for the principal BRCT contrast), and formal equivalence testing (TOST) demonstrated equivalence within a prespecified \u00b120% margin for BRCA1 BRCT (TOST p = 0.031). Heterogeneity across cohorts was minimal (Cochran\u2019s Q = 0.62, I2 = 0.0%). Descriptive analyses of VUSs suggested the apparent enrichment of BRCA1 BRCT-localized missense variants in TNBC (31.8% vs. 17.9% in HR+), but this signal did not extend to pathogenic mutations. Conclusions: Within the statistical power available, our three-cohort analysis shows no evidence of large subtype-specific enrichment of pathogenic BRCA1\/2 somatic mutations across protein domains or cluster regions; small to moderate effects cannot be excluded. Notably, the majority (64%) of pathogenic mutations occurred in HR+\/HER2\u2212 disease, underscoring that BRCA1\/2 testing should not be deprioritized in non-TNBC subtypes. The apparent BRCT enrichment observed in earlier unfiltered analyses appears to be driven by VUSs rather than pathogenic variants, highlighting the methodological necessity of pathogenicity filtering for clinically actionable inference. These findings provide cohort-scale supportive evidence for emerging clinical guidelines that recommend broader BRCA1\/2 testing across breast cancer subtypes.<\/jats:p>","DOI":"10.3390\/genes17060693","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T05:56:31Z","timestamp":1781675791000},"page":"693","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Domain-Level Distribution of Pathogenic BRCA1\/2 Somatic Mutations Shows No Evidence of Large Subtype-Specific Enrichment in Breast Cancer: A Three-Cohort Analysis Supporting Broad BRCA Testing"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1991-6620","authenticated-orcid":false,"given":"Elif","family":"Sertesen \u00c7am\u00f6z","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, University of Health Sciences, Ankara 06200, Turkey"},{"name":"Department of Medical Genetics, Ba\u015fkent University, Ankara 06490, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatih","family":"Y\u0131ld\u0131z","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, University of Health Sciences, Ankara 06200, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mutlu","family":"Dogan","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, University of Health Sciences, Ankara 06200, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5612-9696","authenticated-orcid":false,"given":"Yunus Kas\u0131m","family":"Terzi","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Ba\u015fkent University, Ankara 06490, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zerrin","family":"Y\u0131lmaz \u00c7elik","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Ba\u015fkent University, Ankara 06490, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nrc3181","article-title":"BRCA1 and BRCA2: Different roles in a common pathway of genome protection","volume":"12","author":"Roy","year":"2011","journal-title":"Nat. Rev. Cancer."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1126\/science.1252230","article-title":"Cancer suppression by the chromosome custodians, BRCA1 and BRCA2","volume":"343","author":"Venkitaraman","year":"2014","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1056\/NEJMoa1706450","article-title":"Olaparib for metastatic breast cancer in patients with a germline BRCA mutation","volume":"377","author":"Robson","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1056\/NEJMoa1802905","article-title":"Talazoparib in patients with advanced breast cancer and a germline BRCA mutation","volume":"379","author":"Litton","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1093\/jnci\/djt095","article-title":"Cancer risks for BRCA1 and BRCA2 mutation carriers: Results from prospective analysis of EMBRACE","volume":"105","author":"Mavaddat","year":"2013","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.6004\/jnccn.2023.0051","article-title":"NCCN Guidelines Insights: Genetic\/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2024","volume":"21","author":"Daly","year":"2023","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.annonc.2022.10.004","article-title":"Risk reduction and screening of cancer in hereditary breast-ovarian cancer syndromes: ESMO Clinical Practice Guideline","volume":"34","author":"Sessa","year":"2023","journal-title":"Ann. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/35021093","article-title":"Molecular portraits of human breast tumours","volume":"406","author":"Perou","year":"2000","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1093\/jnci\/djg050","article-title":"Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer","volume":"95","author":"Foulkes","year":"2003","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1158\/1055-9965.EPI-11-0775","article-title":"Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: Results from the Consortium of Investigators of Modifiers of BRCA1\/2 (CIMBA)","volume":"21","author":"Mavaddat","year":"2012","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.1001\/jama.2017.7112","article-title":"Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers","volume":"317","author":"Kuchenbaecker","year":"2017","journal-title":"JAMA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.1200\/JCO.20.00299","article-title":"Management of hereditary breast cancer: ASCO, ASTRO, and SSO Guideline","volume":"38","author":"Tung","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1200\/JCO.18.01631","article-title":"Underdiagnosis of hereditary breast cancer: Are genetic testing guidelines a tool or an obstacle?","volume":"37","author":"Beitsch","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e201204005","DOI":"10.5936\/csbj.201204005","article-title":"Structure-function of the tumor suppressor BRCA1","volume":"1","author":"Clark","year":"2012","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.tibs.2004.09.010","article-title":"Interactions between BRCT repeats and phosphoproteins: Tangled up in two","volume":"29","author":"Glover","year":"2004","journal-title":"Trends Biochem. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1126\/science.297.5588.1837","article-title":"BRCA2 function in DNA binding and recombination from a BRCA2\u2013DSS1\u2013ssDNA structure","volume":"297","author":"Yang","year":"2002","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/nature01230","article-title":"Insights into DNA recombination from the structure of a RAD51\u2013BRCA2 complex","volume":"420","author":"Pellegrini","year":"2002","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1001\/jama.2014.5985","article-title":"Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer","volume":"313","author":"Rebbeck","year":"2015","journal-title":"JAMA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.ccell.2026.03.003","article-title":"Cancer type-specific variation in patterns of driver alterations across 50,000 tumors","volume":"44","author":"Bandlamudi","year":"2026","journal-title":"Cancer Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2394","DOI":"10.1056\/NEJMoa2105215","article-title":"Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer","volume":"384","author":"Tutt","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1634\/theoncologist.2012-0452","article-title":"BRCA1\/2 sequence variants of uncertain significance: A primer for providers to assist in discussions and in medical management","volume":"18","author":"Lindor","year":"2013","journal-title":"Oncologist"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/humu.21628","article-title":"ENIGMA\u2014Evidence-based Network for the Interpretation of Germline Mutant Alleles: An international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes","volume":"33","author":"Spurdle","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"pl1","DOI":"10.1126\/scisignal.2004088","article-title":"Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal","volume":"6","author":"Gao","year":"2013","journal-title":"Sci. Signal."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.cell.2015.09.033","article-title":"Comprehensive molecular portraits of invasive lobular breast cancer","volume":"163","author":"Ciriello","year":"2015","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1038\/nature10983","article-title":"The genomic and transcriptomic architecture of 2000 breast tumours reveals novel subgroups","volume":"486","author":"Curtis","year":"2012","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11479","DOI":"10.1038\/ncomms11479","article-title":"The somatic mutation profiles of 2,433 breast cancers refine their genomic and transcriptomic landscapes","volume":"7","author":"Pereira","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1038\/s41586-024-08167-5","article-title":"Automated real-world data integration improves cancer outcome prediction","volume":"636","author":"Jee","year":"2024","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cels.2018.03.002","article-title":"Scalable open science approach for mutation calling of tumor exomes using multiple genomic pipelines","volume":"6","author":"Ellrott","year":"2018","journal-title":"Cell Syst."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.jmoldx.2014.12.006","article-title":"Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): A hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology","volume":"17","author":"Cheng","year":"2015","journal-title":"J. Mol. Diagn."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Cheng, D.T., Prasad, M., Chekaluk, Y., Benayed, R., Sadowska, J., Zehir, A., Syed, A., Wang, Y.E., Somar, J., and Li, Y. (2017). Comprehensive detection of germline variants by MSK-IMPACT, a clinical diagnostic platform for solid tumor molecular oncology and concurrent cancer predisposition testing. BMC Med. Genom., 10.","DOI":"10.1186\/s12920-017-0271-4"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Cline, M.S., Liao, R.G., Parsons, M.T., Paten, B., Alquaddoomi, F., Antoniou, A., Baxter, S., Brody, L., Cook-Deegan, R., and Coffin, A. (2018). BRCA Challenge: BRCA Exchange as a global resource for variants in BRCA1 and BRCA2. PLoS Genet., 14.","DOI":"10.1371\/journal.pgen.1007752"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41586-018-0461-z","article-title":"Accurate classification of BRCA1 variants with saturation genome editing","volume":"562","author":"Findlay","year":"2018","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1093\/annonc\/mdv278","article-title":"BRCA1 and BRCA2 genetic testing\u2014Pitfalls and recommendations for managing variants of uncertain clinical significance","volume":"26","author":"Eccles","year":"2015","journal-title":"Ann. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/s41523-018-0066-6","article-title":"Migrating the SNP array-based homologous recombination deficiency measures to next generation sequencing data of breast cancer","volume":"4","author":"Sztupinszki","year":"2018","journal-title":"NPJ Breast Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1016\/j.annonc.2022.09.159","article-title":"Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1\/2 and high-risk, early breast cancer","volume":"33","author":"Geyer","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_38","first-page":"125","article-title":"Tandem duplication and triplication in BRCA1: Revisiting the large genomic rearrangements via optical genome mapping","volume":"296\u2013297","author":"Wendeburg","year":"2025","journal-title":"Cancer Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1080\/1354750X.2025.2591717","article-title":"Emerging biomarkers in breast cancer: Translational and multi-omics perspectives in precision oncology","volume":"30","author":"Yasmin","year":"2025","journal-title":"Biomarkers"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1159\/000540419","article-title":"Complete response to pembrolizumab in a patient with castration-resistant prostate cancer with both BRCA positivity and a high frequency of microsatellite instability: A case report","volume":"17","author":"Hirano","year":"2024","journal-title":"Case Rep. Oncol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/6\/693\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T06:13:40Z","timestamp":1781676820000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/6\/693"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,13]]},"references-count":40,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["genes17060693"],"URL":"https:\/\/doi.org\/10.3390\/genes17060693","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,13]]}}}