Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR)
Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR)
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DOI：
10.1002/humu.20735
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发表时间：
2008-06-01
期刊：
影响因子：
3.9
通讯作者：
Lipkin, Steven M.
中科院分区：
文献类型：
--
作者：
Chao, Elizabeth C.;Velasquez, Jonathan L.;Lipkin, Steven M.
Lynch综合征，也称为遗传性非息肉病性结肠癌（HNPCC），是已知的结直肠癌（CRC）最常见的遗传综合征。MLH 1/MSH 2突变是大约90%的Lynch综合征家族的基础。这些突变中有24%是错义突变。解释错义变异是极具挑战性的。因此，我们开发了蛋白质多态性错配修复的多变量分析（MAPP-MMR），这是一种生物信息学算法，可有效地将MLH 1/MSH 2有害和中性错义变体分类。我们编制了一个大型MLH 1/MSH 2错义变体数据库（n>300），并具有相关的临床和分子特征。我们将该数据库划分为不重叠的训练集和验证集，并测试了MAPP-MMR。MAPP-MMR显著优于其他错义变体分类算法（灵敏度94%;特异性96%;阳性预测值[PPV] 98%;阴性预测值[NPV] 89%），如SIFT和PolyPhen。MAPP-MMR是用于错义变体解释的有效生物信息学工具，其准确区分MLH 1/MSH 2有害变体与中性变体。
Lynch syndrome, also known as hereditary nonpolyposis colon cancer (HNPCC), is the most common known genetic syndrome for colorectal cancer (CRC). MLH1/MSH2 mutations underlie approximately 90% of Lynch syndrome families. A total of 24% of these mutations are missense. Interpreting missense variation is extremely challenging. We have therefore developed multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR), a bioinformatic algorithm that effectively classifies MLH1/MSH2 deleterious and neutral missense variants. We compiled a large database (n>300) of MLH1/MSH2 missense variants with associated clinical and molecular characteristics. We divided this database into nonoverlapping training and validation sets and tested MAPP-MMR. MAPP-MMR significantly outperformed other missense variant classification algorithms (sensitivity, 94%; specificity, 96%; positive predictive value [PPV] 98%; negative predictive value [NPV], 89%), such as SIFT and PolyPhen. MAPP-MMR is an effective bioinformatic tool for missense variant interpretation that accurately distinguishes MLH1/MSH2 deleterious variants from neutral variants.