Clinical phenotypes combined with saturation genome editing identifying the pathogenicity of BRCA1 variants of uncertain significance in breast cancer

AbstractCharacterizing the pathogenicity ofBRCA1 variants of uncertain significance (VUSs) is a major bottleneck in clinical management ofBRCA1-associated breast cancer. Saturation genome editing (SGE) was recently reported as an innovative laboratory-based approach to assess the pathogenicity ofBRCA1 variants. We combined clinical phenotypes and SGE score to identify the pathogenicity ofBRCA1 VUSs detected in a cohort of 8,085 breast cancer patients. According to SGE function score, 33 out of 144BRCA1 VUSs detected were classified into “loss of function” (n = 13), “intermediate” (n = 2), and “functional” (n = 18) groups. Compared with non-carriers, “loss of function” VUS carriers (n = 19) presented significantly worse clinicopathological characteristics. These included younger age at breast cancer d iagnosis (44.4 years vs. 51.2 years,P = 0.01), stronger family history of any cancer (57.9% vs. 32.3%,P = 0.017) especially breast or ovarian cancer (47.4% vs. 9.3%,P <  0.001), more bilateral breast cancer (31.6% vs. 3.4%,P <  0.001), and triple-negative breast cancer (47.4% vs. 12.8%,P <  0.001), which were comparable to those of pathogenic variant carriers. In contrast, the clinical phenotypes of “functional” VUS carriers were similar to those of non-carriers. These results indicated that SGE was a reliable method inBRCA1 variant classification. Combining SGE function score and the available evidence, twelve out ...
Source: Familial Cancer - Category: Cancer & Oncology Source Type: research