BRCA1 氨基端 2172 个变异的 DNA 修复功能评分。
DNA repair function scores for 2172 variants in the BRCA1 amino-terminus.
机构信息
The Ohio State University, Department of Biomedical Informatics, Columbus, Ohio, United States of America.
The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America.
出版信息
PLoS Genet. 2023 Aug 14;19(8):e1010739. doi: 10.1371/journal.pgen.1010739. eCollection 2023 Aug.
Single nucleotide variants are the most frequent type of sequence changes detected in the genome and these are frequently variants of uncertain significance (VUS). VUS are changes in DNA for which disease risk association is unknown. Thus, methods that classify the functional impact of a VUS can be used as evidence for variant interpretation. In the case of the breast and ovarian cancer specific tumor suppressor protein, BRCA1, pathogenic missense variants frequently score as loss of function in an assay for homology-directed repair (HDR) of DNA double-strand breaks. We previously published functional results using a multiplexed assay for 1056 amino acid substitutions residues 2-192 in the amino terminus of BRCA1. In this study, we have re-assessed the data from this multiplexed assay using an improved analysis pipeline. These new analysis methods yield functional scores for more variants in the first 192 amino acids of BRCA1, plus we report new results for BRCA1 amino acid residues 193-302. We now present the functional classification of 2172 BRCA1 variants in BRCA1 residues 2-302 using the multiplexed HDR assay. Comparison of the functional determinations of the missense variants with clinically known benign or pathogenic variants indicated 93% sensitivity and 100% specificity for this assay. The results from BRCA1 variants tested in this assay are a resource for clinical geneticists for evidence to evaluate VUS in BRCA1.
单核苷酸变异是基因组中最常见的序列变化类型,这些变异通常是意义不明的变异(VUS)。VUS 是指 DNA 中的变异,其疾病风险关联未知。因此,能够对 VUS 的功能影响进行分类的方法可以用作变异解释的证据。在乳腺癌和卵巢癌特异性肿瘤抑制蛋白 BRCA1 的情况下,致病性错义变异在用于同源定向修复(HDR)的 DNA 双链断裂的测定中经常表现为功能丧失。我们之前使用针对 BRCA1 氨基末端 2-192 位氨基酸的 1056 个氨基酸取代残基的多重测定法发表了功能结果。在这项研究中,我们使用改进的分析管道重新评估了来自该多重测定法的数据。这些新的分析方法为 BRCA1 氨基末端的前 192 个氨基酸中的更多变体提供了功能评分,并且我们还报告了 BRCA1 氨基酸残基 193-302 的新结果。我们现在使用多重 HDR 测定法对 BRCA1 残基 2-302 中的 2172 个 BRCA1 变体进行了功能分类。将错义变体的功能测定与临床上已知的良性或致病性变体进行比较,表明该测定法的敏感性为 93%,特异性为 100%。在该测定法中测试的 BRCA1 变体的结果为临床遗传学家提供了评估 BRCA1 中的 VUS 的证据。