BRCA1/BRCA2 Test Results Show Widely Varying Breast, Ovarian Cancer Risk

A retrospective cohort study of nearly 16,000 females who underwent BRCA1 or BRCA2 testing in Ontario, Canada, found that lifetime breast and ovarian cancer risk varied substantially by genetic test result, with elevated risk extending even to individuals with inconclusive or negative findings, according to results published in JAMA Network Open.¹

Among carriers of pathogenic or likely pathogenic (P/LP) variants, cumulative incidence of breast cancer to age 80 years was 62.1% (95% CI, 52.2%-69.9%) for BRCA1 carriers and 66.1% (95% CI, 57.5%-72.9%) for BRCA2 carriers, compared with 12.0% (95% CI, 11.2%-12.8%) in the matched general population. Corresponding lifetime ovarian cancer risk was 56.0% (95% CI, 40.0%-67.7%) for BRCA1 carriers and 29.3% (95% CI, 14.2%-41.7%) for BRCA2 carriers, vs 1.5% (95% CI, 1.3%-1.7%) in the general population.

Individuals with a variant of uncertain significance (VUS) or a noninformative negative result also had elevated lifetime breast cancer risk—31.2% (95% CI, 19.2%-41.4%) and 26.3% (95% CI, 23.0%-29.4%), respectively—roughly double that of the general population, though neither group showed increased ovarian cancer risk. Individuals with a predictive negative result (a true negative for a known familial variant) had breast cancer risk similar to the general population, at 13.1% (95% CI, 8.8%-17.2%).

Study Design

The analysis drew on the What Comes Next Cohort Study, a near-population-based cohort built through linkage with administrative health databases at ICES, an independent research institute in Ontario. Investigators matched female participants who underwent BRCA1 or BRCA2 testing at 1 of 2 regional genetic testing laboratories between January 2007 and April 2016 to unrelated females from the general population who had not undergone testing, at a ratio of 1:5, based on birth year, household income quintile, and urban or rural residence.¹

Of 15,986 individuals in the full cohort, 6966 were eligible for breast cancer analyses (matched to 34,830 general-population comparators, for 41,796 total) and 13,276 were eligible for ovarian cancer analyses (matched to 66,380 comparators, for 79,656 total). Participants were followed through September 2024, for a median follow-up of 11 years.

Family History Further Stratifies Risk

Among P/LP variant carriers, breast cancer risk rose with family history: those with at least 2 affected first-degree relatives reached a cumulative incidence of 86.3% (95% CI, 70.9%-93.5%), compared with 55.8% (95% CI, 45.4%-64.2%) among carriers with no affected first-degree relatives.¹ A similar pattern held for ovarian cancer among individuals with positive test results, whose risk rose to 64.2% (95% CI, 37.0%-79.7%) with at least 1 affected first-degree relative, compared with 38.2% (95% CI, 25.8%-48.4%) without.

Clinical Context and Limitations

The study's breast cancer risk estimates for P/LP carriers were somewhat lower, and its ovarian cancer estimates somewhat higher, than those reported in a 2017 meta-analysis of more than 9000 variant carriers, which estimated cumulative risk to age 80 years at 72% and 69% for breast cancer and 44% and 17% for ovarian cancer among BRCA1 and BRCA2 carriers, respectively.² The study authors noted that this variation may reflect differences in variant spectrum, penetrance, or use of risk-reducing interventions across cohorts.

The authors also acknowledged that the study did not capture multigene panel testing, limiting its ability to attribute residual risk in the VUS and negative-result groups to variants in genes beyond BRCA1 and BRCA2, and that family history was assessed only at the time of testing rather than accounting for total family size.

According to the study authors, the findings support “individualized risk assessment and management beyond test results alone,” particularly for individuals with VUS or negative results who meet high-risk testing criteria based on personal or family history.¹

REFERENCES

1. Dossa F, Metcalfe K, Ante Z, Liu N, Lerner-Ellis J, Eisen A, Baxter NN. Breast and ovarian cancer among individuals undergoing BRCA1 and BRCA2 testing. JAMA Netw Open. 2026;9(7):e2626334. doi:10.1001/jamanetworkopen.2026.26334

2. Kuchenbaecker KB, Hopper JL, Barnes DR, et al; BRCA1 and BRCA2 Cohort Consortium. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402-2416. doi:10.1001/jama.2017.7112