Risks and Implications of Multiple Actionable Pathogenic Germline Variants Discovered by Panel-Based Cancer Predisposition Testing.

PURPOSE: Growing use of multigene panels (MGPs) is increasing the number of patients identified with multiple pathogenic germline variants (PGVs) in cancer predisposition genes. This study characterizes the landscape of patients with multiple PGVs and identifies clinical settings where multiple PGVs affect management. MATERIALS AND METHODS: This is a single-institution retrospective cohort analysis comprising patients seen in the Department of Clinical Genetics and consented to the Risk Assessment Program (RAP) Registry who were evaluated with a MGP and found to have multiple PGVs. RESULTS: All patients tested between January 1, 2014, and January 1, 2024, and found to have multiple PGV are included. Sixty-four patients (64/7,961, 0.8%) from 58 families carried multiple PGVs, 22/64 (34%) patients carried at least two PGVs in high- or moderate-risk genes, and 33/64 (52%) carried at least two PGVs that result in potential management changes. Five percent (30/557) of all patients with a PGV in BRCA1 or BRCA2 also carried an additional PGV, while 7% (19/284) of patients with a PGV in a mismatch repair (MMR) gene also carried an additional PGV. Ten patients from nine unrelated families had both a PGV in BRCA1 or BRCA2 as well as a PGV in an MMR gene. CONCLUSION: Although the overall percentage of patients undergoing clinical genetic testing with multiple PGVs is small, a significant fraction of these patients could benefit from medical management changes because of the identification of multiple PGVs.