Reclassification of BRCA1 and BRCA2 variants found in ovarian epithelial, fallopian tube, and primary peritoneal cancers

Abstract

Objective We investigated the proportions of and reclassified BRCA1/2 variants of unknown significance (VUS) in Korean patients with epithelial ovarian, tubal, and primary peritoneal cancers. Methods Data from 805 patients who underwent genetic testing for BRCA1/2 from January 1, 2006 to August 31, 2018 were included. The VUS in BRCA1/2 were reclassified using the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines. Results A BRCA1 pathogenic variant was found in 17.0% (137/805) of the patients, and BRCA1 VUS were found in 15.9% (128/805) of the patients. Further, 8.7% (69/805) of the patients possessed a BRCA2 pathogenic variant and 18.4% (148/805) of the patients possessed BRCA2 VUS. Fifty-three specific BRCA1 VUS were found and 20 were further reclassified as benign (n=11), likely benign (n=5), likely pathogenic (n=3), and pathogenic (n=1). The remaining 33 remained classified as VUS. For BRCA2 , 55 specific VUS were detected; among these, 14 were reclassified as benign or likely benign, and 2 were reclassified as likely pathogenic. Among the 805 patients, 195 were found to have only VUS and no pathogenic variants (PV), and 41.5% (81/195) were reclassified as benign or likely benign, and 10.3% (20/195) as pathogenic or likely pathogenic variants. Conclusions Approximately 33.3% (36/108) of the specific BRCA1/2 variants analyzed in this study that were initially classified as VUS over a 13-year period were reclassified. Among these, 5.6% (6/108) were reclassified as pathogenic or likely pathogenic variants.

Protective operative techniques in radical hysterectomy in early cervical carcinoma and their influence on disease-free and overall survival: a systematic review and meta-analysis of risk groups

“…In their single-arm study, they reached high 10-year OS and DFS rates (93.1 and 95.8%, respectively). These results are supported by the publication of Kong et al, who described a HR of 3.059 (95% CI 1.176–7.958; p = 0.022) [ 22 ] for risk of recurrence when intracorporal instead of vaginal colpotomy was performed.…”

Differences in Ovarian and Other Cancers Risks by Population and BRCA Mutation Location

“…Table 1 shows the differences in germline BRCA1/2 mutation prevalence between population and country in ovarian cancer patients [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. The frequency of germline BRCA mutation ranged from 5% to 30%.…”

“…In many mutational analyses of BRCA1/2 genes for epithelial ovarian cancer, we picked up large-scale epidemiological studies of more than 500 ovarian cancer patients. Table 2 shows that the rate of germline BRCA mutation of each histological type varies by the country where the study was conducted [ 28 , 29 , 30 , 34 , 35 , 36 , 37 , 38 ]. Regarding high-grade serous carcinoma, the mutation rate showed a range of 16% to 28%, and the rate tended to be higher in Asian countries than in Western countries.…”

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer, Part 1: Technical Considerations

“…Although recent years have led to an improved understanding of the functions and molecular alterations of BRCA1/2 (and consequently to more accurate classifications), discrepancies still exist within databases [ 139 , 140 , 141 ]. While the accumulation of data led to important refinements in the classification of BRCA mutations, and despite the synchronization of classification according to guidelines and data sharing, reclassification still frequently occurs [ 142 ]. In addition to clear pathogenic variants, “likely pathogenic” variants are frequently included in RCTs and in FDA/EMA approval, although the latter does not result in absolute proof of its pathogenic nature.…”