Somatic Profiling Prospectively Guides Germline Genetic Testing in Patients with Mutations in High-Risk Cancer Predisposition Genes

In Brief: While approximately 15% of patients with advanced cancer have an inherited predisposition to malignancy, many patients who carry a pathogenic germline variant do not qualify for genetic testing based on current clinical guidelines. Offering genetic testing to those patients with the highest likelihood of carrying a germline mutation is preferable to unselected screening. In this study, investigators used a tiered gene list to help identify patients whose somatic mutations were more likely to be found in the germline. Genes were classified into 3 tiers based on the likelihood of germline pathogenicity. Patients whose routine somatic sequencing tests revealed a mutation that was classified as high-risk (tier 1) were offered participation in this study. Enrolled patients received standard genetic counseling and were offered germline genetic testing via a commercial laboratory next-generation sequencing panel. In all, 9.2% of somatic sequencing tests harbored a high-risk (tier 1) gene mutation; an inherited predisposition to cancer was confirmed in almost 50% of patients enrolled in the study. Patients with gastrointestinal or brain cancers that displayed a high-risk variant were more likely to be confirmed as having a germline mutation than were those with other cancer types. These findings support expanding clinical criteria and lowering barriers for germline genetic testing in patients with advanced cancer.