Reinterpretation of BRCA1 and BRCA2 variants of uncertain significance in patients with hereditary breast/ovarian cancer using the ACMG/AMP 2015 guidelines

Background Although BRCA1 or BRCA2 ( BRCA1 / 2 ) genetic testing plays an important role in determining treatment modalities in patients with hereditary breast and ovarian cancer, sequence variants with unknown clinical significance or variant of uncertain significance (VUS) have limited use in medical decision-making. With vast quantities of gene-related data being updated, the clinical significance of VUS may change over time. We reinterpreted the sequence variant previously reported as BRCA1 / 2 VUS results in patients with breast or ovarian cancer and assessed whether the clinical significance of VUS was changed. Methods We retrospectively reviewed medical records of 423 breast or ovarian cancer patients who underwent BRCA1 / 2 genetic testing from 2010 to 2017. The VUSs in BRCA1 / 2 were reanalyzed using the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines (ACMG/AMP 2015 guidelines) and the VUS was reclassified into five categories: “pathogenic”, “likely pathogenic”, “VUS”, “likely benign”, and “benign”. Results A total of 75 patients (48 sequence types of VUS) were identified as carrying either one or more VUS in BRCA1 / 2 . Among the 75 patients, two patients (2.7%) were reclassified as “likely pathogenic”, 30 patients (40.0%) were reclassified as either “benign” or “likely benign”, and the remaining 43 patients (57.3%) were still classified as VUS category. Conclusions Since the clinical significance of VUS in BRCA1 / 2 may vary from time to time, reinterpretation of the VUS results could contribute to clinical decision-making.