A negative BRCA1 or BRCA2 test does not necessarily place a woman at the same breast cancer risk as the general population, according to a large Canadian study that is challenging how genetic test results are interpreted. Researchers found that women who tested negative for a cancer-associated BRCA mutation still faced an estimated 25% lifetime risk of breast cancer—nearly twice the approximately 13% lifetime risk for women in the general population. The findings, published in JAMA Network Open, suggest that family history may remain a powerful risk signal even when testing does not identify a harmful BRCA mutation.
The study examined health records from nearly 16,000 women in Ontario who underwent BRCA testing between 2007 and 2016. The participants were not randomly selected from the general population. Most had been referred for testing because of a personal or family history of breast, ovarian or related cancers, a known mutation in their family, or ancestry associated with elevated hereditary cancer risk. This distinction is important: a negative result in a woman already considered high risk does not necessarily erase the clinical information that prompted testing in the first place.
BRCA1 and BRCA2 are tumor-suppressor genes involved in repairing damaged DNA. When certain inherited mutations impair their function, cells can accumulate genetic errors more readily, increasing the probability that a tumor will develop. Women carrying a harmful mutation in one of these genes may face a lifetime breast cancer risk estimated at roughly 30% to 70%, depending on the gene, the specific variant and other biological and environmental factors. Yet the absence of a detectable mutation does not mean that all inherited or familial risk has been excluded.
Among women in the Ontario cohort who tested negative for a pathogenic BRCA mutation, the estimated lifetime risk of breast cancer was 25%. The estimated risk was even higher—30%—for women whose test revealed a variant of uncertain significance, or VUS. A VUS is a genetic alteration for which available evidence is insufficient to determine whether it affects gene function or cancer susceptibility. Such findings are not considered proof of increased risk and generally should not be used alone to guide irreversible medical decisions, but the women in this study remained part of a clinically high-risk population because of the circumstances that led to testing.
The researchers also found that family history substantially changed risk estimates within every genetic test category. Among women who tested positive for a BRCA mutation, lifetime breast cancer risk ranged from approximately 56% to 86%, depending on how many first-degree relatives had been diagnosed with breast or ovarian cancer. First-degree relatives include parents, siblings and children, whose shared genetic background provides a particularly informative measure of inherited susceptibility. The results reinforce the idea that a genetic test is not a complete risk assessment; it is one component of a broader calculation that includes family patterns, age, reproductive history and other factors.
“The future cancer risk for these women has not been well studied,” said Fahima Dossa, MD, PhD, a surgical oncologist at Cedars-Sinai Cancer and lead author of the study. She said the findings could help clinicians guide all women who undergo BRCA testing, rather than treating a negative result as a universal return to average risk. In practical terms, physicians may combine genetic findings with detailed family histories and validated risk models to determine whether a patient needs earlier or more frequent mammography, supplemental breast MRI, genetic counseling or discussion of preventive options.
The study illustrates why a negative result can have different meanings depending on the reason for testing. A woman who has a known familial BRCA mutation and tests negative specifically for that mutation may have a risk closer to that of the general population, because the familial cause has been identified and excluded for her. By contrast, a woman with several close relatives affected by breast cancer who receives a negative result on a broader BRCA test may still carry other inherited risk factors that current testing did not detect or that have not yet been scientifically characterized.
For patients, the distinction between “negative,” “uninformative negative” and “variant of uncertain significance” can be crucial. A negative result means that no harmful mutation covered by the test was identified, not that the person has no genetic susceptibility. An uninformative negative result occurs when testing fails to explain a strong family cancer pattern. Genetic counseling can help determine whether additional testing, updated analysis or screening based on family history is appropriate. At the same time, the researchers emphasize that test results should be interpreted by qualified clinicians and should not automatically lead to preventive surgery or other major interventions.
The study was supported by ICES, the Ontario Ministry of Health and Ministry of Long-Term Care, the Canadian Cancer Society and the Canadian Institutes of Health Research. Its observational design means that it can estimate cancer incidence within a large tested population but cannot prove that family history alone caused the elevated risk. The findings nevertheless provide new evidence that hereditary cancer assessment must move beyond a single gene result. As genetic testing expands, the central message is becoming increasingly difficult to ignore: a negative BRCA test may close one investigative path, but it does not necessarily close the question of breast cancer risk.
Subject of Research: Breast and ovarian cancer risk among women undergoing BRCA1 and BRCA2 genetic testing
Article Title: Incidence of Breast and Ovarian Cancer Among Women Undergoing BRCA1 and BRCA2 Testing
News Publication Date: 30-Jul-2026
Web References: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/10.1001/jamanetworkopen.2026.26334
References: Dossa F, Metcalfe K, Ante Z, Liu N, Lerner-Ellis J, Eisen A, Baxter NN. “Incidence of Breast and Ovarian Cancer Among Women Undergoing BRCA1 and BRCA2 Testing.” JAMA Network Open. DOI: 10.1001/jamanetworkopen.2026.26334
Keywords: BRCA1, BRCA2, breast cancer, ovarian cancer, genetic testing, hereditary cancer, family history, variant of uncertain significance, cancer risk, genetic counseling
