When Angelina Jolie revealed in 2013 that she carried a pathogenic BRCA1 variant and had undergone a preventive double mastectomy, genetic testing for hereditary breast and ovarian cancer surged into public consciousness. Yet a sweeping new analysis of more than 15 years of testing data from Estonia now suggests that even within families already touched by these cancers, the true prevalence of dangerous variants is dramatically underestimated—and that men, in particular, are being left out of a conversation that could save their lives.
Researchers from the University of Tartu examined the genetic testing records of 3,472 healthy individuals who were referred between 2007 and 2023 because a close relative had breast or ovarian cancer. The results, published in Frontiers in Genetics, show that 19.7 percent of these ostensibly healthy family members harbored a pathogenic or likely pathogenic variant known to significantly elevate cancer risk. Among the men who were tested, the rate was even more striking: 34 percent carried a high‑risk variant, with BRCA2 mutations especially prominent—a finding that directly challenges the widespread assumption that hereditary cancer syndromes are primarily a women’s health issue.
“Hereditary cancer risk is both more common and more actionable than often assumed,” said lead author Dr. Mikk Tooming of the Institute of Clinical Medicine. “People with a family history of breast or ovarian cancer—especially those with multiple affected relatives or early‑onset cases—should strongly consider genetic counselling and, where appropriate, genetic testing.” Tooming and his colleagues emphasize that the high detection rate they observed, including the substantial proportion of carriers identified before the typical screening age, implies that relying solely on standard population screening may delay the recognition of elevated risk.
The Estonian cohort was overwhelmingly female—87.6 percent—because referral practices have historically focused on women. Yet among the 12.4 percent of participants who were men, the positivity rate was nearly double that seen in the cohort as a whole. Male carriers of pathogenic variants, particularly in BRCA2, face sharply increased lifetime risks for prostate, pancreatic and breast cancers, and may benefit from earlier and more intensive surveillance, such as prostate‑specific antigen (PSA) monitoring beginning in their forties. The study’s authors argue that the systematic under‑inclusion of men represents a missed opportunity for early detection and prevention.
The age profile of those tested was equally revealing. The mean age at testing was 41, a full decade below Estonia’s standard cancer screening starting age, and more than 78 percent of participants were younger than the national screening threshold. Alarmingly, individuals under 30 years old were the most likely to test positive for a pathogenic variant. At the same time, dangerous variants were still being detected in people over 71, the age at which routine screening is often discontinued, underscoring that genetic risk assessment has value across the entire adult lifespan.
When the researchers stratified participants by whether a family member already carried a known variant, the numbers became even starker. Among the roughly one‑third of participants with a previously identified familial mutation, 41.8 percent tested positive for the same variant. In the remaining two‑thirds—those with a suggestive family history but no known molecular lesion—8 percent nonetheless carried a pathogenic variant. This finding, Tooming noted, strongly supports broader access to multigene panel testing, which can unmask hereditary risk even when a specific familial mutation has not yet been characterized.
The study tracked 23 distinct pathogenic variants across multiple genes, but the classic BRCA1 and BRCA2 genes accounted for nearly 59 percent of all detected mutations. The data also highlighted how technological advances have reshaped detection rates: after next‑generation sequencing became widely available in Estonia around 2015, the proportion of individuals found to carry a pathogenic variant increased noticeably, suggesting that many earlier tests returned false‑negative results due to the limitations of older, single‑gene sequencing methods.
The clinical implications of such findings extend well beyond genetic curiosity. Carriers of high‑risk variants can pursue tailored risk‑management strategies that range from intensified imaging—earlier and more frequent mammography or breast MRI—to risk‑reducing surgeries such as prophylactic mastectomy or salpingo‑oophorectomy. Even for moderate‑risk variants, the knowledge can shift the timing and modality of screening. “Such decisions are highly individual and should always be made in the context of genetic counselling, taking into account personal risk, age, and preferences,” Tooming cautioned. He pointed out that the study’s detection rate among relatives of mutation carriers is high enough to justify cascade testing not only in first‑degree relatives but also in more distant family members, a practice that remains inconsistently implemented worldwide.
The research team is careful to acknowledge limitations: the cohort spans a period during which both the accessibility and quality of testing evolved dramatically, from just three individuals tested in 2007 to 731 in 2023. The reliance on clinical referral patterns means the sample is not representative of the general population, and the results may not directly translate to other countries with different genetic backgrounds and healthcare infrastructures. Nevertheless, the Estonian data provide some of the most compelling real‑world evidence to date that systematic genetic risk assessment in cancer‑affected families uncovers far more actionable findings than current screening paradigms capture.
Tooming envisions a future in which population‑based genetic screening moves beyond narrow family‑history criteria, male participation in testing becomes a public health priority, and functional studies illuminate the biological impact of less common or moderate‑risk variants. “Our data show that a substantial proportion of pathogenic variant carriers are identified before the typical screening age,” he said. “Relying solely on standard population screening may delay detection of elevated risk.” As the cost of comprehensive genetic testing continues to fall, the Estonian experience makes a powerful case for rewriting the rules of who gets tested and when.
Subject of Research: People
News Publication Date: July 7, 2026
Web References: http://dx.doi.org/10.3389/fgene.2026.1814500
References: Frontiers in Genetics, 2026, DOI: 10.3389/fgene.2026.1814500
