Accurate classification of MLH1/MSH2 missense variants with Multivariate Analysis of Protein Polymorphisms-Mismatch Repair (MAPP-MMR) Academic Article uri icon


MeSH Major

  • Adaptor Proteins, Signal Transducing
  • Adenocarcinoma
  • Colorectal Neoplasms, Hereditary Nonpolyposis
  • Databases, Genetic
  • MutS Homolog 2 Protein
  • Mutation, Missense
  • Nuclear Proteins


  • 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.

publication date

  • June 2008



  • Academic Article



  • eng

Digital Object Identifier (DOI)

  • 10.1002/humu.20735

PubMed ID

  • 18383312

Additional Document Info

start page

  • 852

end page

  • 60


  • 29


  • 6