Researchers sought to determine new BRIP1 variants related to inherited colorectal cancer. For this purpose, they assessed affected as well as nonaffected persons from 18 familial colorectal cancer Type X (FCCTX) or high-risk microsatellite-stable (MSS) colorectal cancer families via whole-exome sequencing. They also employed a next-generation sequencing multigene panel to screen another 62 colorectal cancer patients from FCCTX or high-risk MSS colorectal cancer families. Experts discovered three different BRIP1 mutations in three unrelated families. Of those, two were frameshift variants [c.1702_1703del, p.(Asn568TrpfsTer9) and c.903del, p.(Leu301PhefsTer2)] that led to truncation of the protein and were therefore classified as pathogenic (class 5). The third one was a missense variant [c.2220G>T, p.(Gln740His)] regarded as a variant of uncertain significance (class 3). Evidence associating the two BRIP1 frameshift variants with colorectal cancer risk was afforded by segregation and loss-of-heterozygosity studies, with suggestive though not definitive evidence that the third variant may be benign. Overall, experts inferred that there could exist an association between germline BRIP1e pathogenic variants and hereditary colorectal cancer predisposition. Source
