Reclassification of BRCA1 and BRCA2 Variants of Unknown Significance in a Turkish Cohort; A Single-Center, Retrospective Study.

Accurate classification of breast cancer susceptibility gene (BRCA)1/2 variants is important to delineate candidates for surgical or medical treatment. We retrospectively analyzed BRCA1/BRCA2 sequencing data and reclassified the BRCA1/2 variants of unknown significance (VUS) in Turkish patients with breast, ovarian, pancreatic and prostate cancers. BRCA1/BRCA2 sequence data of a large cohort were retrospectively analyzed. The sequencing data were reinterpreted in the context of American College of Medical Genetics guidelines, the Evidence-based Network for the Interpretation of Germline Mutant Alleles BRCA1/2 classification rules, and current public genomic databases. Among the total of 2,713 patients, 254 (9.36%) had BRCA1 or BRCA2 variants. A total of 264 BRCA1/BRCA2 variants were detected. Of these, 130 (49.2%) were pathogenic variants (PV), 24 (9%) were likely pathogenic (LP) and 110 of 264 variants (41.6%) were VUS. For the 119 BRCA1 variants, 68% (n = 81) were PV, 7.5% (n = 9) were LP, and 24.5% (n = 29) were VUS. Similarly, for the 145 BRCA2 variants, 33.7% (n = 49) were PV, 10.3% (n = 15) were LP, and 55.8% (n = 81) were VUS. Reanalysis of the 110 BRCA1+BRCA2 VUS variants led to 22 (20%) being reclassified. Of these 22, 45.4% (n = 10) were reclassified as P/LP and 54.6% (n = 12) were reclassified as benign/likely benign. These results show that it may be possible to reclassify VUS, in this case BRCA1/2 VUS, in light of changing genetic data. These results demonstrate the importance of VUS reclassification of BRCA1/2 variants in clinical management, surgical decisions, risk counseling and screening.