Large-Scale Functional Analysis and Evaluation of Pathogenicity in BRCA2
摘要
Germline pathogenic variants of BRCA2 are significantly associated with a high risk of several cancers. Although genetic testing allows for individual risk management, the large number of variants of uncertain significance (VUSs) identified through genetic testing poses a significant challenge to clinical utility. Owing to insufficient clinical evidence to determine the pathogenicity of these variants, various in vitro assays must be developed. Various functional evaluations have been performed using assays based on the different functions of BRCA2. These data were considered as strong evidence for interpreting the pathogenicity of VUSs. The accumulation of functional data from these assays has enabled significant progress in addressing the VUSs. However, several issues remain regarding the clinical application of functional annotations. Here, we summarize several functional assays for the reclassification of VUSs and the contribution of functionally abnormal variants to cancer risk. Subsequently, we discuss the challenges in the clinical utility of functional data and future studies that could overcome these challenges.