Clinical Management of Patients at Risk for Hereditary Breast Cancer with Variants of Uncertain Significance in the Era of Multigene Panel Testing

Background: Rising use of multigene panel testing has led to increased identification of variants of uncertain significance (VUS). Consensus guidelines state that clinicians should not make medical management decisions based on VUS findings. We sought to analyze how VUS affect management of patients at risk for hereditary breast cancer. Methods: All genetic testing reports for indications of hereditary breast cancer risk from a single tertiary-care institution from 2015 to 2018 were reviewed. Variants were grouped by pathogenicity (benign/likely benign, VUS, or pathogenic/likely pathogenic [P/LP]) and by breast cancer susceptibility (high, moderate, or none). Patient and management characteristics were compared by variant pathogenicity and breast cancer risk. Results: Overall, 563 patients underwent genetic testing for breast cancer risk; 336 VUS were identified in 228 (40.5%) of patients of which 26.4% were in high or moderate penetrance genes. P/LP results were found in 61 (10.8%) patients, of which 61.2% were identified in breast-specific moderate and high penetrance genes, and 38.7% were found in non-breast specific genes. Of variants found in high-risk genes, 54.5% were P/LP and 45.5% were VUS. On multivariable analysis, prophylactic mastectomy was associated with younger age and personal history of cancer, but not variant pathogenicity or penetrance. There were no differences in the use of post-test imaging, oophorectomy, or colonoscopy based on variant findings or age. Conclusions: In this era of multigene panel testing, genetic factors help to inform, but not dictate, complex decision-making in surveillance and management of patients at risk for hereditary breast cancer.