DNA repair function scores for 2172 variants in the BRCA1 amino-terminus.
DNA repair function scores for 2172 variants in the BRCA1 amino-terminus.
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DOI：
10.1371/journal.pgen.1010739
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发表时间：
2023-08
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
单核苷酸变异是基因组中检测到的最常见的序列变化类型，这些变异通常是不确定意义的变异（VUS）。VUS是DNA的变化，其疾病风险关联尚不清楚。因此，对VUS的功能影响进行分类的方法可以作为变体解释的证据。在乳腺癌和卵巢癌特异性肿瘤抑制蛋白BRCA1的情况下，在DNA双链断裂的同源性定向修复（HDR）检测中，致病性错义变异体经常被评分为功能丧失。我们之前发表了对BRCA1氨基端1056个氨基酸取代残基2-192进行多重分析的功能结果。在这项研究中，我们使用改进的分析管道重新评估了该多路分析的数据。这些新的分析方法为BRCA1前192个氨基酸的更多变异提供了功能评分，此外，我们报告了BRCA1氨基酸残基193-302的新结果。我们现在使用多路HDR分析，对BRCA1残基2-302中的2172个BRCA1变异进行了功能分类。将错义变异与临床已知的良性或致病性变异的功能测定结果进行比较，表明该检测方法的灵敏度为93%，特异性为100%。该检测中检测的BRCA1变异的结果为临床遗传学家评估BRCA1中VUS的证据提供了资源。BRCA1中的大多数错义替换是未知意义的变异（VUS）， BRCA1中具有VUS的个体不能仅从遗传信息中知道该变异是否易患乳腺癌或卵巢癌。我们应用同源定向修复DNA双链断裂的多重功能分析来评估变异对这一重要BRCA1蛋白功能的影响。我们分析了BRCA1氨基末端的2172个变异，并证明在DNA修复试验中，已知的致病性变异具有功能丧失。相反，已知的良性变异在多重检测中功能正常。我们建议，这些BRCA1变异的功能测定可用于增加临床癌症遗传学家为BRCA1 VUS患者提供的信息。
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. Most missense substitutions in BRCA1 are variants of unknown significance (VUS), and individuals with a VUS in BRCA1 cannot know from genetic information alone whether this variant predisposes to breast or ovarian cancer. We apply a multiplexed functional assay for homology directed repair of DNA double strand breaks to assess variant impact on this important BRCA1 protein function. We analyzed 2172 variants in the amino-terminus of BRCA1 and demonstrate that variants that are known as pathogenic have a loss of function in the DNA repair assay. Conversely, variants that are known to be benign are functionally normal in the multiplexed assay. We suggest that these functional determinations of BRCA1 variants can be used to augment the information that clinical cancer geneticists provide to patients who have a VUS in BRCA1.
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