Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions.
Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions.
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DOI：
10.1002/humu.22214
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发表时间：
2013-01
期刊：
影响因子：
3.9
通讯作者：
Tavtigian, Sean V.
中科院分区：
文献类型：
--
作者：
Thompson, Bryony A.;Greenblatt, Marc S.;Vallee, Maxime P.;Herkert, Johanna C.;Tessereau, Chloe;Young, Erin L.;Adzhubey, Ivan A.;Li, Biao;Bell, Russell;Feng, Bingjian;Mooney, Sean D.;Radivojac, Predrag;Sunyaev, Shamil R.;Frebourg, Thierry;Hofstra, Robert M. W.;Sijmons, Rolf H.;Boucher, Ken;Thomas, Alun;Goldgar, David E.;Spurdle, Amanda B.;Tavtigian, Sean V.
在用于患者管理的基因检测过程中观察到的罕见错义替换的分类是临床遗传学中的一个相当大的问题。未分类变异的贝叶斯综合评估是最初为 BRCA1/2 开发的解决方案。在这里，我们向错配修复 (MMR) 基因（MLH1、MSH2、MSH6 和 PMS2）的类似系统迈出了一步，通过在计算机中校准工具来估计 MMR 基因错义替换的先验致病性概率，该系统赋予林奇综合征结肠癌易感性。开发了定性五级分类系统并将其应用于 143 个 MMR 错义变体。这确定了 74 个适合校准的错义替换。使用六种不同的计算机工具（Align-Grantham Variation Grantham Deviation、蛋白质多态性多变量分析 [MAPP]、Mut-Pred、PolyPhen-2.1、从耐受性中排序不耐受性和 Xvar）对这些替换进行评分，并尽可能使用策划的 MMR 多序列比对。每个工具的输出均通过针对 74 个错义替换的分类进行回归来校准；这些校准输出可解释为致病性的先验概率。 MAPP 是最准确的工具，MAPP + PolyPhen-2.1 提供了最佳组合模型（R2 = 0.62，接收器操作特性下的面积 = 0.93）。 MAPP + PolyPhen-2.1 输出具有足够的预测能力，可以作为连续变量输入到 MMR 基因错义替换临床分类的定量贝叶斯综合评估中。
Classification of rare missense substitutions observed during genetic testing for patient management is a considerable problem in clinical genetics. The Bayesian integrated evaluation of unclassified variants is a solution originally developed for BRCA1/2. Here, we take a step toward an analogous system for the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) that confer colon cancer susceptibility in Lynch syndrome by calibrating in silico tools to estimate prior probabilities of pathogenicity for MMR gene missense substitutions. A qualitative five-class classification system was developed and applied to 143 MMR missense variants. This identified 74 missense substitutions suitable for calibration. These substitutions were scored using six different in silico tools (Align-Grantham Variation Grantham Deviation, multivariate analysis of protein polymorphisms [MAPP], Mut-Pred, PolyPhen-2.1, Sorting Intolerant From Tolerant, and Xvar), using curated MMR multiple sequence alignments where possible. The output from each tool was calibrated by regression against the classifications of the 74 missense substitutions; these calibrated outputs are interpretable as prior probabilities of pathogenicity. MAPP was the most accurate tool and MAPP + PolyPhen-2.1 provided the best-combined model (R2 = 0.62 and area under receiver operating characteristic = 0.93). The MAPP + PolyPhen-2.1 output is sufficiently predictive to feed as a continuous variable into the quantitative Bayesian integrated evaluation for clinical classification of MMR gene missense substitutions.
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