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

Elizabeth C. Chao, Jonathan L. Velasquez, Mavee S L Witherspoon, Laura S. Rozek, David Peel, Pauline Ng, Stephen B. Gruber, Patrice Watson, Gad Rennert, Hoda Anton-Culver, Henry T. Lynch, Steven M. Lipkin

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)852-860
Number of pages9
JournalHuman Mutation
Volume29
Issue number6
DOIs
StatePublished - Jun 2008

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DNA Mismatch Repair
Hereditary Nonpolyposis Colorectal Neoplasms
Multivariate Analysis
Computational Biology
Proteins
Databases
Missense Mutation
Colorectal Neoplasms
Mutation

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Chao, E. C., Velasquez, J. L., Witherspoon, M. S. L., Rozek, L. S., Peel, D., Ng, P., ... Lipkin, S. M. (2008). Accurate classification of MLH1/MSH2 missense variants with Multivariate Analysis of Protein Polymorphisms-Mismatch Repair (MAPP-MMR). Human Mutation, 29(6), 852-860. https://doi.org/10.1002/humu.20735

Accurate classification of MLH1/MSH2 missense variants with Multivariate Analysis of Protein Polymorphisms-Mismatch Repair (MAPP-MMR). / 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 T.; Lipkin, Steven M.

In: Human Mutation, Vol. 29, No. 6, 06.2008, p. 852-860.

Research output: Contribution to journalArticle

Chao, EC, Velasquez, JL, Witherspoon, MSL, Rozek, LS, Peel, D, Ng, P, Gruber, SB, Watson, P, Rennert, G, Anton-Culver, H, Lynch, HT & Lipkin, SM 2008, 'Accurate classification of MLH1/MSH2 missense variants with Multivariate Analysis of Protein Polymorphisms-Mismatch Repair (MAPP-MMR)', Human Mutation, vol. 29, no. 6, pp. 852-860. https://doi.org/10.1002/humu.20735
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 T. ; Lipkin, Steven M. / Accurate classification of MLH1/MSH2 missense variants with Multivariate Analysis of Protein Polymorphisms-Mismatch Repair (MAPP-MMR). In: Human Mutation. 2008 ; Vol. 29, No. 6. pp. 852-860.
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