Integrated evaluation of DNA sequence variants of unknown clinical significance:: Application to BRCA1 and BRCA2
Integrated evaluation of DNA sequence variants of unknown clinical significance:: Application to BRCA1 and BRCA2
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DOI：
10.1086/424388
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发表时间：
2004-10-01
影响因子：
9.8
通讯作者：
Couch, FJ
中科院分区：
文献类型：
--
作者：
Goldgar, DE;Easton, DF;Couch, FJ
易感基因中的许多序列变异具有不确定的临床意义，将这些变异分为高风险或低风险类别是临床遗传学中的一个重要问题。此类变体的分类可以通过直接流行病学观察来进行，包括与家族中疾病的共分离和疾病家族史的程度，或通过间接测量来进行，包括氨基酸保守性、氨基酸变化的严重性和来自功能测定的证据。在这项研究中，我们已经开发出一种方法来合成这样的证据在多因素似然比模型。我们应用该模型分析了BRCA1和BRCA2中的三种未分类变体。证据强烈表明，两种变异（BRCA1中的C1787 S和BRCA2中的D2723 H）是有害的，三种（BRCA1中的R841 W和BRCA2中的Y42 C和P655 R）是中性的，一种（BRCA1中的R1699 Q）仍然具有不确定的意义。这些结果证明了该模型的实用性。
Many sequence variants in predisposition genes are of uncertain clinical significance, and classification of these variants into high- or low-risk categories is an important problem in clinical genetics. Classification of such variants can be performed by direct epidemiological observations, including cosegregation with disease in families and degree of family history of the disease, or by indirect measures, including amino acid conservation, severity of amino acid change, and evidence from functional assays. In this study, we have developed an approach to the synthesis of such evidence in a multifactorial likelihood-ratio model. We applied this model to the analysis of three unclassified variants in BRCA1 and three in BRCA2. The evidence strongly suggests that two variants (C1787S in BRCA1 and D2723H in BRCA2) are deleterious, three (R841W in BRCA1 and Y42C and P655R in BRCA2) are neutral, and one (R1699Q in BRCA1) remains of uncertain significance. These results provide a demonstration of the utility of the model.