Calibration of Multiple In Silico Tools for Predicting Pathogenicity of Mismatch Repair Gene Missense Substitutions
Identifieur interne : 004B02 ( Main/Exploration ); précédent : 004B01; suivant : 004B03Calibration of Multiple In Silico Tools for Predicting Pathogenicity of Mismatch Repair Gene Missense Substitutions
Auteurs : Bryony A. Thompson [Australie] ; Marc S. Greenblatt ; Maxime P. Vallee [France] ; Johanna C. Herkert [Pays-Bas] ; Chloe Tessereau [France] ; Erin L. Young ; Ivan A. Adzhubey [États-Unis] ; Biao Li ; Russell Bell ; Bingjian Feng ; Sean D. Mooney ; Predrag Radivojac ; Shamil R. Sunyaev [États-Unis] ; Thierry Frebourg [France] ; Robert M. W. Hofstra [Pays-Bas] ; Rolf H. Sijmons [Pays-Bas] ; Ken Boucher ; Alun Thomas ; David E. Goldgar ; Amanda B. Spurdle [Australie] ; Sean V. Tavtigian [États-Unis]Source :
- Human Mutation [ 1059-7794 ] ; 2013-01.
Descripteurs français
- Wicri :
- topic : Génétique.
English descriptors
- KwdEn :
- Alignment, Assay, Bayesian, Binary, Bivariate, Chao, Continuous variables, Curated, Curated alignments, Default conditions, Easton, Gene missense substitutions, Gene variants, General population, Genetic variants, Genetics, Goldgar, Greenblatt, Human mutation, Independent tumors, Individual sequences, Insight mutation interpretation committee, Least squares regression, Least squares regressions, Logistic regression, Mapp, Mapp output, Mismatch, Mismatch repair, Mismatch repair genes, Missense, Missense substitution, Missense substitutions, Missense variants, Mlh1, Modest changes, Msh2, Msh6, Multiple sequence alignments, Multivariate analysis, Mutat, Mutation, Mutpred, Native alignments, Online version, Ordinal, Pathogenic, Pathogenicity, Plon, Pms2, Posterior probability, Program scores, Protein function, Qualitative class, Regression, Salt lake city, Sequence alignment, Sequence alignments, Sequence variant, Silico, Silico predictions, Silico scores, Silico tool, Silico tools, Statistical analyses, Substitution, Tavtigian, Trinary, Tumor characteristics, Utah school, Variant, Xvar.
- Teeft :
- Alignment, Assay, Bayesian, Binary, Bivariate, Chao, Continuous variables, Curated, Curated alignments, Default conditions, Easton, Gene missense substitutions, Gene variants, General population, Genetic variants, Genetics, Goldgar, Greenblatt, Human mutation, Independent tumors, Individual sequences, Insight mutation interpretation committee, Least squares regression, Least squares regressions, Logistic regression, Mapp, Mapp output, Mismatch, Mismatch repair, Mismatch repair genes, Missense, Missense substitution, Missense substitutions, Missense variants, Mlh1, Modest changes, Msh2, Msh6, Multiple sequence alignments, Multivariate analysis, Mutat, Mutation, Mutpred, Native alignments, Online version, Ordinal, Pathogenic, Pathogenicity, Plon, Pms2, Posterior probability, Program scores, Protein function, Qualitative class, Regression, Salt lake city, Sequence alignment, Sequence alignments, Sequence variant, Silico, Silico predictions, Silico scores, Silico tool, Silico tools, Statistical analyses, Substitution, Tavtigian, Trinary, Tumor characteristics, Utah school, Variant, Xvar.
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 (R2 = 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.
Url:
- https://api.istex.fr/document/38C44BD09451A105FC9F193C4DC5E092C6ACBA65/fulltext/pdf
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318556
DOI: 10.1002/humu.22214
Affiliations:
- Australie, France, Pays-Bas, États-Unis
- Auvergne-Rhône-Alpes, Groningue (province), Haute-Normandie, Hollande-Méridionale, Massachusetts, Rhône-Alpes, Région Normandie
- Boston, Groningue, Lyon, Rotterdam, Rouen
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Le document en format XML
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Hofstra</name><affiliation wicri:level="3"><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Clinical Genetics, Erasmus MC, Rotterdam</wicri:regionArea><placeName><settlement type="city">Rotterdam</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Sijmons, Rolf H" sort="Sijmons, Rolf H" uniqKey="Sijmons R" first="Rolf H." last="Sijmons">Rolf H. Sijmons</name><affiliation wicri:level="3"><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department Genetics, University Medical Center Groningen, Groningen</wicri:regionArea><placeName><settlement type="city">Groningue</settlement><region nuts="2" type="province">Groningue (province)</region></placeName></affiliation></author><author><name sortKey="Boucher, Ken" sort="Boucher, Ken" uniqKey="Boucher K" first="Ken" last="Boucher">Ken Boucher</name><affiliation><wicri:noCountry code="subField">City</wicri:noCountry></affiliation></author><author><name sortKey="Thomas, Alun" sort="Thomas, Alun" uniqKey="Thomas A" first="Alun" last="Thomas">Alun Thomas</name><affiliation><wicri:noCountry code="subField">City</wicri:noCountry></affiliation></author><author><name sortKey="Goldgar, David E" sort="Goldgar, David E" uniqKey="Goldgar D" first="David E." last="Goldgar">David E. Goldgar</name><affiliation><wicri:noCountry code="subField">City</wicri:noCountry></affiliation></author><author><name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B." last="Spurdle">Amanda B. Spurdle</name><affiliation wicri:level="1"><country xml:lang="fr">Australie</country><wicri:regionArea>Queensland Institute of Medical Research, Brisbane, Herston</wicri:regionArea><wicri:noRegion>Herston</wicri:noRegion></affiliation></author><author><name sortKey="Tavtigian, Sean V" sort="Tavtigian, Sean V" uniqKey="Tavtigian S" first="Sean V." last="Tavtigian">Sean V. Tavtigian</name><affiliation></affiliation><affiliation></affiliation><affiliation wicri:level="1"><country wicri:rule="url">États-Unis</country></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Human Mutation</title><title level="j" type="alt">HUMAN MUTATION</title><idno type="ISSN">1059-7794</idno><idno type="eISSN">1098-1004</idno><imprint><biblScope unit="vol">34</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="255">255</biblScope><biblScope unit="page" to="265">265</biblScope><biblScope unit="page-count">11</biblScope><date type="published" when="2013-01">2013-01</date></imprint><idno type="ISSN">1059-7794</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1059-7794</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Alignment</term><term>Assay</term><term>Bayesian</term><term>Binary</term><term>Bivariate</term><term>Chao</term><term>Continuous variables</term><term>Curated</term><term>Curated alignments</term><term>Default conditions</term><term>Easton</term><term>Gene missense substitutions</term><term>Gene variants</term><term>General population</term><term>Genetic variants</term><term>Genetics</term><term>Goldgar</term><term>Greenblatt</term><term>Human mutation</term><term>Independent tumors</term><term>Individual sequences</term><term>Insight mutation interpretation committee</term><term>Least squares regression</term><term>Least squares regressions</term><term>Logistic regression</term><term>Mapp</term><term>Mapp output</term><term>Mismatch</term><term>Mismatch repair</term><term>Mismatch repair genes</term><term>Missense</term><term>Missense substitution</term><term>Missense substitutions</term><term>Missense variants</term><term>Mlh1</term><term>Modest changes</term><term>Msh2</term><term>Msh6</term><term>Multiple sequence alignments</term><term>Multivariate analysis</term><term>Mutat</term><term>Mutation</term><term>Mutpred</term><term>Native alignments</term><term>Online version</term><term>Ordinal</term><term>Pathogenic</term><term>Pathogenicity</term><term>Plon</term><term>Pms2</term><term>Posterior probability</term><term>Program scores</term><term>Protein function</term><term>Qualitative class</term><term>Regression</term><term>Salt lake city</term><term>Sequence alignment</term><term>Sequence alignments</term><term>Sequence variant</term><term>Silico</term><term>Silico predictions</term><term>Silico scores</term><term>Silico tool</term><term>Silico tools</term><term>Statistical analyses</term><term>Substitution</term><term>Tavtigian</term><term>Trinary</term><term>Tumor characteristics</term><term>Utah school</term><term>Variant</term><term>Xvar</term></keywords><keywords scheme="Teeft" xml:lang="en"><term>Alignment</term><term>Assay</term><term>Bayesian</term><term>Binary</term><term>Bivariate</term><term>Chao</term><term>Continuous variables</term><term>Curated</term><term>Curated alignments</term><term>Default conditions</term><term>Easton</term><term>Gene missense substitutions</term><term>Gene variants</term><term>General population</term><term>Genetic variants</term><term>Genetics</term><term>Goldgar</term><term>Greenblatt</term><term>Human mutation</term><term>Independent tumors</term><term>Individual sequences</term><term>Insight mutation interpretation committee</term><term>Least squares regression</term><term>Least squares regressions</term><term>Logistic regression</term><term>Mapp</term><term>Mapp output</term><term>Mismatch</term><term>Mismatch repair</term><term>Mismatch repair genes</term><term>Missense</term><term>Missense substitution</term><term>Missense substitutions</term><term>Missense variants</term><term>Mlh1</term><term>Modest changes</term><term>Msh2</term><term>Msh6</term><term>Multiple sequence alignments</term><term>Multivariate analysis</term><term>Mutat</term><term>Mutation</term><term>Mutpred</term><term>Native alignments</term><term>Online version</term><term>Ordinal</term><term>Pathogenic</term><term>Pathogenicity</term><term>Plon</term><term>Pms2</term><term>Posterior probability</term><term>Program scores</term><term>Protein function</term><term>Qualitative class</term><term>Regression</term><term>Salt lake city</term><term>Sequence alignment</term><term>Sequence alignments</term><term>Sequence variant</term><term>Silico</term><term>Silico predictions</term><term>Silico scores</term><term>Silico tool</term><term>Silico tools</term><term>Statistical analyses</term><term>Substitution</term><term>Tavtigian</term><term>Trinary</term><term>Tumor characteristics</term><term>Utah school</term><term>Variant</term><term>Xvar</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Génétique</term></keywords></textClass></profileDesc></teiHeader><front><div type="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 (R2 = 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.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li><li>Pays-Bas</li><li>États-Unis</li></country><region><li>Auvergne-Rhône-Alpes</li><li>Groningue (province)</li><li>Haute-Normandie</li><li>Hollande-Méridionale</li><li>Massachusetts</li><li>Rhône-Alpes</li><li>Région Normandie</li></region><settlement><li>Boston</li><li>Groningue</li><li>Lyon</li><li>Rotterdam</li><li>Rouen</li></settlement></list><tree><noCountry><name sortKey="Bell, Russell" sort="Bell, Russell" uniqKey="Bell R" first="Russell" last="Bell">Russell Bell</name><name sortKey="Boucher, Ken" sort="Boucher, Ken" uniqKey="Boucher K" first="Ken" last="Boucher">Ken Boucher</name><name sortKey="Feng, Bingjian" sort="Feng, Bingjian" uniqKey="Feng B" first="Bingjian" last="Feng">Bingjian Feng</name><name sortKey="Goldgar, David E" sort="Goldgar, David E" uniqKey="Goldgar D" first="David E." last="Goldgar">David E. Goldgar</name><name sortKey="Greenblatt, Marc S" sort="Greenblatt, Marc S" uniqKey="Greenblatt M" first="Marc S." last="Greenblatt">Marc S. Greenblatt</name><name sortKey="Li, Biao" sort="Li, Biao" uniqKey="Li B" first="Biao" last="Li">Biao Li</name><name sortKey="Mooney, Sean D" sort="Mooney, Sean D" uniqKey="Mooney S" first="Sean D." last="Mooney">Sean D. Mooney</name><name sortKey="Radivojac, Predrag" sort="Radivojac, Predrag" uniqKey="Radivojac P" first="Predrag" last="Radivojac">Predrag Radivojac</name><name sortKey="Thomas, Alun" sort="Thomas, Alun" uniqKey="Thomas A" first="Alun" last="Thomas">Alun Thomas</name><name sortKey="Young, Erin L" sort="Young, Erin L" uniqKey="Young E" first="Erin L." last="Young">Erin L. Young</name></noCountry><country name="Australie"><noRegion><name sortKey="Thompson, Bryony A" sort="Thompson, Bryony A" uniqKey="Thompson B" first="Bryony A." last="Thompson">Bryony A. Thompson</name></noRegion><name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B." last="Spurdle">Amanda B. Spurdle</name><name sortKey="Thompson, Bryony A" sort="Thompson, Bryony A" uniqKey="Thompson B" first="Bryony A." last="Thompson">Bryony A. Thompson</name></country><country name="France"><region name="Auvergne-Rhône-Alpes"><name sortKey="Vallee, Maxime P" sort="Vallee, Maxime P" uniqKey="Vallee M" first="Maxime P." last="Vallee">Maxime P. Vallee</name></region><name sortKey="Frebourg, Thierry" sort="Frebourg, Thierry" uniqKey="Frebourg T" first="Thierry" last="Frebourg">Thierry Frebourg</name><name sortKey="Tessereau, Chloe" sort="Tessereau, Chloe" uniqKey="Tessereau C" first="Chloe" last="Tessereau">Chloe Tessereau</name></country><country name="Pays-Bas"><region name="Groningue (province)"><name sortKey="Herkert, Johanna C" sort="Herkert, Johanna C" uniqKey="Herkert J" first="Johanna C." last="Herkert">Johanna C. Herkert</name></region><name sortKey="Hofstra, Robert M W" sort="Hofstra, Robert M W" uniqKey="Hofstra R" first="Robert M. W." last="Hofstra">Robert M. W. Hofstra</name><name sortKey="Sijmons, Rolf H" sort="Sijmons, Rolf H" uniqKey="Sijmons R" first="Rolf H." last="Sijmons">Rolf H. Sijmons</name></country><country name="États-Unis"><region name="Massachusetts"><name sortKey="Adzhubey, Ivan A" sort="Adzhubey, Ivan A" uniqKey="Adzhubey I" first="Ivan A." last="Adzhubey">Ivan A. Adzhubey</name></region><name sortKey="Sunyaev, Shamil R" sort="Sunyaev, Shamil R" uniqKey="Sunyaev S" first="Shamil R." last="Sunyaev">Shamil R. Sunyaev</name><name sortKey="Tavtigian, Sean V" sort="Tavtigian, Sean V" uniqKey="Tavtigian S" first="Sean V." last="Tavtigian">Sean V. Tavtigian</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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