A multicenter study of clinical impact of variant of uncertain significance reclassification in breast, ovarian, and colorectal cancer susceptibility genes.

10512 Background: Up to 10% of all cancers are attributable to germline mutations and identifying mutation carriers is critical for cancer prevention. Clinical interpretation of genetic test results is complicated by variants of uncertain significance (VUS) with unknown impact on health, which can be clarified through reclassification. However, there is little empirical evidence regarding VUS reclassification in oncology care settings, including the prevalence and outcomes of reclassification, racial/ethnic differences, and the proportion of patients who undergo cancer preventive healthcare management as a result of VUS reclassification. Methods: Retrospective analysis of persons carrying VUS (with or without an accompanying pathogenic or likely pathogenic [P/LP] variant) in breast, ovarian, and colorectal cancer genes who underwent genetic counseling at four geographically dispersed cancer care settings (in Texas, Florida, Ohio, and New Jersey) between 2013 and 2019, and followed until 2020. Results: Among 2,715 individuals, 3,261 VUS and 313 P/LP variants were reported and 11% (300/2,715) had a P/LP in addition to VUS. In total, 8.1% of all individuals with VUS experienced reclassifications, 87.1% of which were downgraded to benign or likely benign and 12.9% were upgraded to P/LP. Reclassification rates varied significantly among cancer care settings from 4.81% to 20.19% (overall p < 0.001). The reclassification pattern across genes suggests that VUS in most genes underwent reclassification at a rate proportional to their prevalence in the overall sample and occurred commonly in ATM, BRCA2, BRCA1, and CHEK2. Compared to their prevalence in the sample, reclassification rates were higher for Blacks (13.6% vs 19.0%), lower for Asians (6.3% vs 3.5%), and proportional for Whites and Hispanics. Median time to reclassification decreased steadily between 2014 and 2019 from 3.08 to 0.91 years. Overall, 11.3% of all reclassified VUS resulted in clinically actionable findings and 4.6% subsequently changed individuals’ clinical managements including prophylactic surgeries and intensive screenings for cancer prevention and early detection. Conclusions: In this large multisite study, VUS reclassification changed clinical management for 0.4% of all individuals. VUS reclassification may alter clinical management, has implications for precision cancer prevention, and highlights the need for standardized clinical practice guidelines and policies for returning reclassified results to patients.