{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:59:23Z","timestamp":1791413963245,"version":"4.3.3"},"reference-count":16,"publisher":"American Medical Association (AMA)","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n \n Pathogenic variants in\n BRCA1<\/jats:italic>\n and\n BRCA2<\/jats:italic>\n confer substantial risks of breast and ovarian cancer; however, risk for female individuals undergoing testing, particularly those with variants of uncertain significance (VUS) or negative results, remain poorly defined.\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n To estimate lifetime incidence of breast and ovarian cancer among female individuals undergoing\n BRCA1<\/jats:italic>\n or\n BRCA2<\/jats:italic>\n testing across all result categories and evaluate the modifying association of family history.\n <\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n \n This retrospective cohort study was conducted as part of the What Comes Next Cohort Study, a near\u2013population-based cohort in Ontario, Canada, established through linkage with administrative databases. Female participants who underwent\n BRCA1<\/jats:italic>\n or\n BRCA2<\/jats:italic>\n testing from 2007 to 2016 were matched 1:5 to females from the general population. Participants were followed up to September 2024. Data were analyzed from May to December 2025.\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The outcome of interest was the cumulative incidence of breast and ovarian cancer to age 80 years, stratified by genetic test result and family history.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Of 15\u202f986 individuals in the What Comes Next Cohort Study cohort, 6966 individuals eligible for breast cancer analyses (median [IQR] age, 49 [38-60] years) were matched to 34\u202f830 individuals from the general population and 13\u202f276 individuals eligible for ovarian cancer analyses (median [IQR] age, 51 [41-61] years) were matched to 66\u202f380 individuals from the general population. Cumulative breast cancer incidence to age 80 years was 62.1% (95% CI, 52.2%-69.9%) for\n BRCA1<\/jats:italic>\n pathogenic variant carriers and 66.1% (95% CI, 57.5%-72.9%) for\n BRCA2<\/jats:italic>\n pathogenic variant carriers, compared with 12.0% (95% CI, 11.2%-12.8%) in the general population; corresponding ovarian cancer incidence was 56.0% (95% CI, 40.0%-67.7%) for\n BRCA1<\/jats:italic>\n pathogenic variant carriers and 29.3% (95% CI, 14.2%-41.7%) for\n BRCA2<\/jats:italic>\n pathogenic variant carriers, compared with 1.5% (95% CI, 1.3%-1.7%) in the general population. Family history modified breast cancer risk, reaching a cumulative incidence of 86.3% (95% CI, 70.9%-93.5%) in carriers with at least 2 affected first-degree relatives vs 55.8% (95% CI, 45.4%-64.2%) in carriers without a family history of breast cancer. Among individuals with test results positive for pathogenic variants, lifetime risk of ovarian cancer was similarly modified by family history, reaching 64.2% (95% CI, 37.0%-79.7%) in those with vs 38.2% (95% CI, 25.8%-48.4%) in those without a family history of ovarian cancer. Individuals with VUS and negative test results also had increased lifetime breast cancer risks (31.2% [95% CI, 19.2%-41.4%] and 26.3% [95% CI, 23.0%-29.4%], respectively) but no increase in ovarian cancer risk. Individuals with test results negative for a known familial variant had risks similar to the general population.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n In this cohort study of females who underwent\n BRCA1<\/jats:italic>\n or\n BRCA2<\/jats:italic>\n testing, the lifetime cancer risk varied substantially across\n BRCA<\/jats:italic>\n test result groups and was further modified by family history. Elevated breast cancer risk among individuals with VUS or negative results highlights the need for individualized risk assessment and management beyond genetic test results alone.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2026.26334","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:30:23Z","timestamp":1785425423000},"page":"e2626334","source":"Crossref","is-referenced-by-count":1,"title":["Breast and Ovarian Cancer Among Individuals Undergoing\n BRCA1<\/i>\n and\n BRCA2<\/i>\n Testing"],"prefix":"10.1001","volume":"9","author":[{"given":"Fahima","family":"Dossa","sequence":"first","affiliation":[{"name":"Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Metcalfe","sequence":"additional","affiliation":[{"name":"Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, Ontario, Canada"},{"name":"Women\u2019s College Research Institute, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zharmaine","family":"Ante","sequence":"additional","affiliation":[{"name":"ICES, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Liu","sequence":"additional","affiliation":[{"name":"ICES, Toronto, Ontario, Canada"},{"name":"Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan","family":"Lerner-Ellis","sequence":"additional","affiliation":[{"name":"Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"},{"name":"Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada"},{"name":"Pathology and Laboratory Medicine, Mount Sinai 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