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

Objective: Accurate classification of variants is important to delineate candidates for surgical or medical treatment. We retrospectively analyzed sequencing data and reclassified the variants of unknown significance (VUS) in Turkish patients with breast, ovarian, pancreatic and prostate cancers.

Materials And Methods: 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 classification rules, and current public genomic databases.

Results: Among the total of 2,713 patients, 254 (9.36%) had or variants. A total of 264 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 variants, 68% ( = 81) were PV, 7.5% ( = 9) were LP, and 24.5% ( = 29) were VUS. Similarly, for the 145 variants, 33.7% ( = 49) were PV, 10.3% ( = 15) were LP, and 55.8% ( = 81) were VUS. Reanalysis of the 110 VUS variants led to 22 (20%) being reclassified. Of these 22, 45.4% ( = 10) were reclassified as P/LP and 54.6% ( = 12) were reclassified as benign/likely benign.

Conclusion: These results show that it may be possible to reclassify VUS, in this case VUS, in light of changing genetic data. These results demonstrate the importance of VUS reclassification of variants in clinical management, surgical decisions, risk counseling and screening.