Clinical significance of variants of unknown significance (VUS) in BRCA1/2 genes

Abstract

Germline mutations in the human breast cancer susceptibility genes BRCA1 and BRCA2 are responsible for 30-70% of hereditary breast and ovarian cancer and 5-10% of all breast and ovarian cancers in heterogeneous Caucasian populations. BRCA1 and BRCA2 mutations confer greatly increased risk of breast and ovarian cancer. BRCA 1 and BRCA 2 genes are large genes with 5,592 and 10,254 bp (coding sequence length), and hence there are multiple sites where mutations can occur and recurrent mutations may not be as common A large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but population-specific variation in the distribution of BRCA1 and BRCA2 mutations is well recognized. Most reported disease ?associated alleles of BRCA1 and BRCA2 have been attributed to frame-shift, nonsense, insertions, deletions or splice site alterations that lead to truncation of BRCA1 or BRAC2 proteins. Besides clear pathogenic mutations, many variants (variant of unknown significance, VUS) are also found. Worldwide, VUS account for approximately half of all unique variants detected. However identifications of VUS are being increasingly reported as more studies on different ethnic populations particularly in ethnicities which are still comparatively less tested. Moreover with the use of NGS (Next Generation Sequencing), the detection rate of VUS has been increased in hereditary breast cancers. Whole-genome, whole-exome sequencing and multi-gene panels are gaining popularity in genetic testing, nevertheless, the discovery of VUS with unknown cancer risk remains the main challenge in terms of clinical interpretation and management. With the increasing VUS being found, it is important to define which VUS are likely to be pathogenic. Various techniques use to characterize these VUS are discussed. Experience in Asian Countries will be shared.