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Jump to Key Points Restricting germline genetic testing to patients diagnosed with cancer before age 50 may miss the large majority of all those with inherited pathogenic variants, a new study suggested.
The research, based on germline sequencing of 39,184 unselected patients with solid tumors, found that the age-50 cutoff would miss 72% of all patients harboring a pathogenic variant. That included 68% of those with moderate- or high-penetrance variants, which confer substantially elevated lifetime cancer risks.
“Hereditary cancer can occur at any age, and we should move toward a new standard in which genetic testing is considered for every patient diagnosed with cancer, regardless of age,” said lead study author Zsofia K. Stadler, MD, of Memorial Sloan Kettering (MSK) Cancer Center in New York City.
Traditionally, she said, a cancer diagnosis before age 50 has been considered an early-onset disease and a possible warning sign for an inherited cancer predisposition syndrome. As a result, age 50 has become the common cutoff for germline genetic sequencing.
- Age <50 cutoff would miss 72% of pathogenic germline variants.
- 16.3% of 39,184 solid tumor pts had germline pathogenic variants.
- ~10% carried moderate/high-penetrance variants; 68% missed by age cutoff.
- Late-onset cancers still had ~5% moderate/high-penetrance variant prevalence.
- Universal germline testing may enable cascade testing for relatives.
For the new study, published in Cancer Discovery, Stadler and her colleagues estimated how often the age-50 cutoff may miss cases of inherited genetic risk.
Using the MSK-IMPACT assay, they tested for 94 germline pathogenic variants in DNA isolated from blood or saliva from patients diagnosed with any of 32 cancer types at MSK between 2015 and 2024.
Overall, germline pathogenic variants were found in 6379 patients, or 16.3% of the cohort. Just under 10% of patients harbored a pathogenic variant in a high- or moderate-penetrance gene. Testing only those diagnosed with cancer before age 50 would miss 4601 carriers of any pathogenic variant, or 72%.
The researchers further stratified patients into early-, average-, and late-onset cancers, with an average age at diagnosis of 43 years, 64 years, and 81 years, respectively. Pathogenic variants were more common in younger patients — 18.4% in early-onset disease, 15.6% in average-onset disease, and 12.3% in late-onset disease (P < .001).
Still, the results demonstrate that germline mutations were common even among patients with late-onset disease, about 5% of whom harbored high- or moderate-penetrance variants, Stadler noted.
She cautioned that the patients were predominantly of European and Ashkenazi Jewish ancestry and may not reflect broader population trends. However, more than 8000 were of non-European ancestry, making this “one of the largest diverse cohorts to undergo agnostic germline testing,” Stadler said.
Melissa Frey, MD, gynecologic oncologist who directs the Genetics and Personalized Cancer Prevention Program at Weill Cornell Medicine in New York City, said she “absolutely” agreed that the findings support universal germline genetic testing.
Frey pointed out that identifying a pathogenic variant can initiate cascade genetic testing of family members, regardless of the patient’s age.
“This information can be lifesaving for at-risk relatives who have not yet developed cancer but are unknowingly at increased risk and stand to benefit from enhanced surveillance and risk-reduction strategies,” she said.
Both Stadler and Frey encouraged oncology teams to integrate germline testing into their own practices rather than relying exclusively on referrals to genetics specialists.
“Study after study has demonstrated that when clinicians refer patients [for genetic counseling], a significant proportion of patients never complete testing,” Frey noted.
“By identifying hereditary cancer risk, we have the opportunity to prevent cancers, improve outcomes, and save lives across entire families,” she said.
According to Frey, one long-standing barrier to germline testing has been concern about genetic discrimination. The federal Genetic Information Nondiscrimination Act offers some protection from genetic discrimination in health insurance and employment but has limitations. Frey noted that California just passed legislation expanding such protections to life and disability insurance.
“Other states should follow,” she said.
The study was funded by the National Institutes of Health and MSK Cancer Center. Stadler reported holding intellectual property rights in SOPHiA GENETICS and having an immediate family member who is a co-founder of the Blue Gen Therapeutics Foundation. Frey reported serving as a consultant for WndrHLTH and AMPA Biosciences, Inc.
