Eight Case Studies of Concurrent Pathogenic Mutations Identified in Hereditary Breast and Ovarian Cancer Gene Panel

Objectives: The availability of next-generation sequencing (NGS) and characterization of multiple genes that can increase cancer risk have caused a shift toward multigene panel testing for hereditary cancer. However, the occurrence of concurrent pathogenic mutations and the utility of panels in individuals who have a known mutation in the family is yet to be well evaluated. We reviewed the personal and family histories of patients found to have multiple pathogenic or likely pathogenic mutations when tested clinically for 19 genes for hereditary breast and ovarian cancer and the implications for the patient and his or her family.

Methods: Samples were analyzed with a 19-gene panel that included NGS of ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53. All mutations were classified according to current American College of Medical Genetics and Genomics guidelines.

Results: Seven patients with 2 concurrent mutations and 1 patient with 3 concurrent mutations were identified in the testing of patients with a 19-gene panel for hereditary breast and ovarian cancer. Mutation combinations included: BRCA1 + CHEK2 (3), ATM + BRCA1 (1), ATM + CHEK2 (1), ATM + BRCA2 (1), BRCA1 + PMS2 (1), and BRCA1 + BRIP1 + CHEK2 (1). Four of the 8 patients (50%) underwent panel testing in the setting of 1 known family mutation. Three patients (38%) were the first person in the family to undergo genetic testing. One patient underwent previous genetic testing with a large cancer panel that identified both pathogenic mutations. Two patients (25%) had a personal history of cancer, and 6 of 8 (75%) had no personal history of cancer. Seven of 8 (88%) patients met National Comprehensive Cancer Network criteria for genetic testing for hereditary breast and ovarian cancer based on personal and/or family history.

Conclusions: Identifying patients with multiple clinically actionable mutations may have important medical implications for the patients as well as for family members. These data suggest those at risk for a known family mutation may still be appropriate candidates for multigene panels due to the risk of multiple mutations. Further research on a larger data set is needed to better elucidate this finding.