title: Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions.
abstract: 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 BRCA1/2. Here, we take a step toward an analogous system for the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) 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 (R(2)  = 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.
authors.affiliation: Queensland Institute of Medical Research, Herston, Brisbane, Australia.
authors.forename: Bryony A
authors.initials: BA
authors.lastname: Thompson
authors.forename: Marc S
authors.initials: MS
authors.lastname: Greenblatt
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Vallee
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Herkert
authors.forename: Chloe
authors.initials: C
authors.lastname: Tessereau
authors.forename: Erin L
authors.initials: EL
authors.lastname: Young
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Adzhubey
authors.forename: Biao
authors.initials: B
authors.lastname: Li
authors.forename: Russell
authors.initials: R
authors.lastname: Bell
authors.forename: Bingjian
authors.initials: B
authors.lastname: Feng
authors.forename: Sean D
authors.initials: SD
authors.lastname: Mooney
authors.forename: Predrag
authors.initials: P
authors.lastname: Radivojac
authors.forename: Shamil R
authors.initials: SR
authors.lastname: Sunyaev
authors.forename: Thierry
authors.initials: T
authors.lastname: Frebourg
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.forename: Rolf H
authors.initials: RH
authors.lastname: Sijmons
authors.forename: Ken
authors.initials: K
authors.lastname: Boucher
authors.forename: Alun
authors.initials: A
authors.lastname: Thomas
authors.forename: David E
authors.initials: DE
authors.lastname: Goldgar
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Spurdle
authors.forename: Sean V
authors.initials: SV
authors.lastname: Tavtigian
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics; D001499:Bayes Theorem; D002138:Calibration; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D019295:Computational Biology / Q000145:classification / Q000379:methods* / Q000592:standards; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics; D012044:Regression Analysis; D015203:Reproducibility of Results
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes