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

Characterizing the pathogenicity of BRCA1 variants of uncertain significance (VUSs) is a major bottleneck in clinical management of BRCA1 -associated breast cancer. Saturation genome editing (SGE) was recently reported as an innovative laboratory-based approach to assess the pathogenicity of BRCA1 variants. We combined clinical phenotypes and SGE score to identify the pathogenicity of BRCA1 VUSs detected in a cohort of 8,085 breast cancer patients. According to SGE function score, 33 out of 144 BRCA1 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 diagnosis (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 in BRCA1 variant classification. Combining SGE function score and the available evidence, twelve out of 33 BRCA1 VUSs were reclassified as pathogenic or likely pathogenic variants and one was benign.