title: Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR).
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.
authors.affiliation: Genetic Epidemiology Research Institute, University of California, Irvine, Irvine, California, USA.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Chao
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Velasquez
authors.forename: Mavee S L
authors.initials: MS
authors.lastname: Witherspoon
authors.forename: Laura S
authors.initials: LS
authors.lastname: Rozek
authors.forename: David
authors.initials: D
authors.lastname: Peel
authors.forename: Pauline
authors.initials: P
authors.lastname: Ng
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
authors.forename: Patrice
authors.initials: P
authors.lastname: Watson
authors.forename: Gad
authors.initials: G
authors.lastname: Rennert
authors.forename: Hoda
authors.initials: H
authors.lastname: Anton-Culver
authors.forename: Henry
authors.initials: H
authors.lastname: Lynch
authors.forename: Steven M
authors.initials: SM
authors.lastname: Lipkin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000230:Adenocarcinoma / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D053843:DNA Mismatch Repair; D030541:Databases, Genetic; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D015999:Multivariate Analysis; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein