Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR) |
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Authors: | Chao Elizabeth C Velasquez Jonathan L Witherspoon Mavee S L Rozek Laura S Peel David Ng Pauline Gruber Stephen B Watson Patrice Rennert Gad Anton-Culver Hoda Lynch Henry Lipkin Steven M |
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Affiliation: | Genetic Epidemiology Research Institute, University of California, Irvine, Irvine, California, USA. |
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Abstract: | 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. |
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Keywords: | Lynch syndrome colorectal cancer variants of uncertain significance cancer genetics HNPCC MLH1 MSH |
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