Calibration of Multiple In Silico Tools for Predicting Pathogenicity of Mismatch Repair Gene Missense Substitutions. Issue 1 (22nd October 2012)

• Record Type: Journal Article
• Authors: Thompson, Bryony A.; Greenblatt, Marc S.; Vallee, Maxime P.; Herkert, Johanna C.; Tessereau, Chloe; Young, Erin L.; Adzhubey, Ivan A.; Li, Biao; Bell, Russell; Feng, Bingjian; Mooney, Sean D.; Radivojac, Predrag; Sunyaev, Shamil R.; Frebourg, Thierry; Hofstra, Robert M.W.; Sijmons, Rolf H.; Boucher, Ken; Thomas, Alun; Goldgar, David E.; Spurdle, Amanda B.; Tavtigian, Sean V.
• Is Part Of: Human mutation. Volume 34:Issue 1(2013:Jan.)
• Page Start: 255
• Page End: 265
• Publication Date: 2012-10-22
• Subjects: Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.22214
• Languages: English
• ISSNs: 1059-7794

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>Classification of rare missense substitutions observed during genetic testing for patient management is a considerable problem in clinical genetics. The Bayesian integrated evaluation of unclassified variants is a solution originally developed for <italic>BRCA1/2</italic>. Here, we take a step toward an analogous system for the mismatch repair (MMR) genes (<italic>MLH1</italic>, <italic>MSH2</italic>, <italic>MSH6</italic>, and <italic>PMS2</italic>) that confer colon cancer susceptibility in Lynch syndrome by calibrating in silico tools to estimate prior probabilities of pathogenicity for MMR gene missense substitutions. A qualitative five‐class classification system was developed and applied to 143 MMR missense variants. This identified 74 missense substitutions suitable for calibration. These substitutions were scored using six different in silico tools (Align‐Grantham Variation Grantham Deviation, multivariate analysis of protein polymorphisms [MAPP], MutPred, PolyPhen‐2.1, Sorting Intolerant From Tolerant, and Xvar), using curated MMR multiple sequence alignments where possible. The output from each tool was calibrated by regression against the classifications of the 74 missense substitutions; these calibrated outputs are interpretable as prior probabilities of pathogenicity. MAPP was the most accurate tool and MAPP + PolyPhen‐2.1 provided the best‐combined model (<italic>R</italic><sup>2</sup> = 0.62 and area under receiver operating characteristic = 0.93). The MAPP + PolyPhen‐2.1 output is sufficiently predictive to feed as a continuous variable into the quantitative Bayesian integrated evaluation for clinical classification of MMR gene missense substitutions.</p> </abstract>