Age-Based Genetic Testing May Miss Most Inherited Cancer Risk Variants

Many patients undergo germline genetic testing only when cancer is diagnosed before age 50, potentially missing pathogenic variants in those with average- or late-onset disease. New findings now show that broader germline testing could identify inherited variants that age-based screening may overlook.

Researchers at Memorial Sloan Kettering Cancer Center (New York, NY, USA) evaluated universal germline genetic testing in patients with solid tumors using the MSK-Integrated Mutation Profiling of Actionable Targets assay, known as MSK-IMPACT. The assay analyzed DNA isolated from blood or saliva for 94 germline pathogenic variants associated with inherited cancer risk.

The study included 39,184 patients with solid tumors, regardless of age. Researchers assessed whether inherited cancer risk would be missed if testing were restricted to patients younger than 50. They also classified cancers as early-, average-, or late-onset based on the distribution of age at onset for each cancer type.

Overall, 16.3% of patients carried at least one germline pathogenic variant. If testing had been limited to patients under age 50, 4,601 patients with pathogenic variants would have been excluded. That represented 72% of all patients with pathogenic variants in the study.

Pathogenic variants were found in 18.4% of patients with early-onset cancers, 15.6% of those with average-onset cancers, and 12.3% of those with late-onset cancers. High-penetrance pathogenic variants were found in 9.1%, 5.5%, and 2.6% of these groups, respectively. Moderate-penetrance variants were found in 3.3%, 3.4%, and 2.5%, respectively, and high- and moderate-penetrance variants together occurred in about 9.7% of all patients.

The findings were published in Cancer Discovery on October 8, 2026. The study identified limitations, including its conduct at a single major tertiary cancer center, uneven representation of some cancer types, and a cohort predominantly of European and Ashkenazi Jewish ancestry. The researchers stated that universal germline testing could support treatment insights and more targeted cascade testing of relatives.

“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. Our manuscript shows that relying on age at diagnosis misses a substantial proportion of patients with germline pathogenic variants and provides strong support for moving toward universal germline genetic testing in patients with cancer,” said Luis A. Diaz Jr., M.D., FAACR, co-corresponding author and head of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center.

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Memorial Sloan Kettering Cancer Center