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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Calibration of Multiple In Silico Tools for Predicting Pathogenicity of Mismatch Repair Gene Missense Substitutions</title><author><name sortKey="Thompson, Bryony A" sort="Thompson, Bryony A" uniqKey="Thompson B" first="Bryony A." last="Thompson">Bryony A. Thompson</name><affiliation><nlm:aff id="A1">Queensland Institute of Medical Research, Herston, Brisbane, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A2">School of Medicine, University of Queensland, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Greenblatt, Marc S" sort="Greenblatt, Marc S" uniqKey="Greenblatt M" first="Marc S." last="Greenblatt">Marc S. Greenblatt</name><affiliation><nlm:aff id="A3">Department of Medicine, University of Vermont, Burlington, Vermont</nlm:aff></affiliation></author><author><name sortKey="Vallee, Maxime P" sort="Vallee, Maxime P" uniqKey="Vallee M" first="Maxime P." last="Vallee">Maxime P. Vallee</name><affiliation><nlm:aff id="A4">International Agency for Research on Cancer, Lyon, France</nlm:aff></affiliation></author><author><name sortKey="Herkert, Johanna C" sort="Herkert, Johanna C" uniqKey="Herkert J" first="Johanna C." last="Herkert">Johanna C. Herkert</name><affiliation><nlm:aff id="A5">Department Genetics, University Medical Center Groningen, Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Tessereau, Chloe" sort="Tessereau, Chloe" uniqKey="Tessereau C" first="Chloe" last="Tessereau">Chloe Tessereau</name><affiliation><nlm:aff id="A6">Breast Cancer Genetics—Cancer Research Center of Lyon, UMR INSERM 1052 CNRS 5286, Lyon, France</nlm:aff></affiliation></author><author><name sortKey="Young, Erin L" sort="Young, Erin L" uniqKey="Young E" first="Erin L." last="Young">Erin L. Young</name><affiliation><nlm:aff id="A7">Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah</nlm:aff></affiliation></author><author><name sortKey="Adzhubey, Ivan A" sort="Adzhubey, Ivan A" uniqKey="Adzhubey I" first="Ivan A." last="Adzhubey">Ivan A. Adzhubey</name><affiliation><nlm:aff id="A8">Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts</nlm:aff></affiliation></author><author><name sortKey="Li, Biao" sort="Li, Biao" uniqKey="Li B" first="Biao" last="Li">Biao Li</name><affiliation><nlm:aff id="A9">School of Informatics and Computing, Indiana University, Bloomington, Indiana</nlm:aff></affiliation></author><author><name sortKey="Bell, Russell" sort="Bell, Russell" uniqKey="Bell R" first="Russell" last="Bell">Russell Bell</name><affiliation><nlm:aff id="A7">Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah</nlm:aff></affiliation></author><author><name sortKey="Feng, Bingjian" sort="Feng, Bingjian" uniqKey="Feng B" first="Bingjian" last="Feng">Bingjian Feng</name><affiliation><nlm:aff id="A10">Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah</nlm:aff></affiliation></author><author><name sortKey="Mooney, Sean D" sort="Mooney, Sean D" uniqKey="Mooney S" first="Sean D." last="Mooney">Sean D. Mooney</name><affiliation><nlm:aff id="A11">Buck Institute, Novato, California</nlm:aff></affiliation></author><author><name sortKey="Radivojac, Predrag" sort="Radivojac, Predrag" uniqKey="Radivojac P" first="Predrag" last="Radivojac">Predrag Radivojac</name><affiliation><nlm:aff id="A9">School of Informatics and Computing, Indiana University, Bloomington, Indiana</nlm:aff></affiliation></author><author><name sortKey="Sunyaev, Shamil R" sort="Sunyaev, Shamil R" uniqKey="Sunyaev S" first="Shamil R." last="Sunyaev">Shamil R. Sunyaev</name><affiliation><nlm:aff id="A8">Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts</nlm:aff></affiliation></author><author><name sortKey="Frebourg, Thierry" sort="Frebourg, Thierry" uniqKey="Frebourg T" first="Thierry" last="Frebourg">Thierry Frebourg</name><affiliation><nlm:aff id="A12">Molecular Genetics of Cancer and Neuropsychiatric Disease, U614 Inserm, Rouen University, Rouen, France</nlm:aff></affiliation></author><author><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><affiliation><nlm:aff id="A13">Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands</nlm:aff></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><nlm:aff id="A5">Department Genetics, University Medical Center Groningen, Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Boucher, Ken" sort="Boucher, Ken" uniqKey="Boucher K" first="Ken" last="Boucher">Ken Boucher</name><affiliation><nlm:aff id="A7">Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah</nlm:aff></affiliation></author><author><name sortKey="Thomas, Alun" sort="Thomas, Alun" uniqKey="Thomas A" first="Alun" last="Thomas">Alun Thomas</name><affiliation><nlm:aff id="A14">Department of Internal Medicine, Division of Genetic Epidemiology, University of Utah School of Medicine, Salt Lake City, Utah</nlm:aff></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><nlm:aff id="A10">Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah</nlm:aff></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><nlm:aff id="A1">Queensland Institute of Medical Research, Herston, Brisbane, Australia</nlm:aff></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><nlm:aff id="A7">Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22949387</idno><idno type="pmc">4318556</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318556</idno><idno type="RBID">PMC:4318556</idno><idno type="doi">10.1002/humu.22214</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">002115</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002115</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Calibration of Multiple In Silico Tools for Predicting Pathogenicity of Mismatch Repair Gene Missense Substitutions</title><author><name sortKey="Thompson, Bryony A" sort="Thompson, Bryony A" uniqKey="Thompson B" first="Bryony A." last="Thompson">Bryony A. Thompson</name><affiliation><nlm:aff id="A1">Queensland Institute of Medical Research, Herston, Brisbane, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A2">School of Medicine, University of Queensland, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Greenblatt, Marc S" sort="Greenblatt, Marc S" uniqKey="Greenblatt M" first="Marc S." last="Greenblatt">Marc S. Greenblatt</name><affiliation><nlm:aff id="A3">Department of Medicine, University of Vermont, Burlington, Vermont</nlm:aff></affiliation></author><author><name sortKey="Vallee, Maxime P" sort="Vallee, Maxime P" uniqKey="Vallee M" first="Maxime P." last="Vallee">Maxime P. Vallee</name><affiliation><nlm:aff id="A4">International Agency for Research on Cancer, Lyon, France</nlm:aff></affiliation></author><author><name sortKey="Herkert, Johanna C" sort="Herkert, Johanna C" uniqKey="Herkert J" first="Johanna C." last="Herkert">Johanna C. Herkert</name><affiliation><nlm:aff id="A5">Department Genetics, University Medical Center Groningen, Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Tessereau, Chloe" sort="Tessereau, Chloe" uniqKey="Tessereau C" first="Chloe" last="Tessereau">Chloe Tessereau</name><affiliation><nlm:aff id="A6">Breast Cancer Genetics—Cancer Research Center of Lyon, UMR INSERM 1052 CNRS 5286, Lyon, France</nlm:aff></affiliation></author><author><name sortKey="Young, Erin L" sort="Young, Erin L" uniqKey="Young E" first="Erin L." last="Young">Erin L. Young</name><affiliation><nlm:aff id="A7">Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah</nlm:aff></affiliation></author><author><name sortKey="Adzhubey, Ivan A" sort="Adzhubey, Ivan A" uniqKey="Adzhubey I" first="Ivan A." last="Adzhubey">Ivan A. Adzhubey</name><affiliation><nlm:aff id="A8">Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts</nlm:aff></affiliation></author><author><name sortKey="Li, Biao" sort="Li, Biao" uniqKey="Li B" first="Biao" last="Li">Biao Li</name><affiliation><nlm:aff id="A9">School of Informatics and Computing, Indiana University, Bloomington, Indiana</nlm:aff></affiliation></author><author><name sortKey="Bell, Russell" sort="Bell, Russell" uniqKey="Bell R" first="Russell" last="Bell">Russell Bell</name><affiliation><nlm:aff id="A7">Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah</nlm:aff></affiliation></author><author><name sortKey="Feng, Bingjian" sort="Feng, Bingjian" uniqKey="Feng B" first="Bingjian" last="Feng">Bingjian Feng</name><affiliation><nlm:aff id="A10">Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah</nlm:aff></affiliation></author><author><name sortKey="Mooney, Sean D" sort="Mooney, Sean D" uniqKey="Mooney S" first="Sean D." last="Mooney">Sean D. Mooney</name><affiliation><nlm:aff id="A11">Buck Institute, Novato, California</nlm:aff></affiliation></author><author><name sortKey="Radivojac, Predrag" sort="Radivojac, Predrag" uniqKey="Radivojac P" first="Predrag" last="Radivojac">Predrag Radivojac</name><affiliation><nlm:aff id="A9">School of Informatics and Computing, Indiana University, Bloomington, Indiana</nlm:aff></affiliation></author><author><name sortKey="Sunyaev, Shamil R" sort="Sunyaev, Shamil R" uniqKey="Sunyaev S" first="Shamil R." last="Sunyaev">Shamil R. Sunyaev</name><affiliation><nlm:aff id="A8">Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts</nlm:aff></affiliation></author><author><name sortKey="Frebourg, Thierry" sort="Frebourg, Thierry" uniqKey="Frebourg T" first="Thierry" last="Frebourg">Thierry Frebourg</name><affiliation><nlm:aff id="A12">Molecular Genetics of Cancer and Neuropsychiatric Disease, U614 Inserm, Rouen University, Rouen, France</nlm:aff></affiliation></author><author><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><affiliation><nlm:aff id="A13">Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands</nlm:aff></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><nlm:aff id="A5">Department Genetics, University Medical Center Groningen, Groningen, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Boucher, Ken" sort="Boucher, Ken" uniqKey="Boucher K" first="Ken" last="Boucher">Ken Boucher</name><affiliation><nlm:aff id="A7">Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah</nlm:aff></affiliation></author><author><name sortKey="Thomas, Alun" sort="Thomas, Alun" uniqKey="Thomas A" first="Alun" last="Thomas">Alun Thomas</name><affiliation><nlm:aff id="A14">Department of Internal Medicine, Division of Genetic Epidemiology, University of Utah School of Medicine, Salt Lake City, Utah</nlm:aff></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><nlm:aff id="A10">Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah</nlm:aff></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><nlm:aff id="A1">Queensland Institute of Medical Research, Herston, Brisbane, Australia</nlm:aff></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><nlm:aff id="A7">Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah</nlm:aff></affiliation></author></analytic><series><title level="j">Human mutation</title><idno type="ISSN">1059-7794</idno><idno type="eISSN">1098-1004</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">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], Mut-Pred, 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></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9215429</journal-id><journal-id journal-id-type="pubmed-jr-id">2408</journal-id><journal-id journal-id-type="nlm-ta">Hum Mutat</journal-id><journal-id journal-id-type="iso-abbrev">Hum. Mutat.</journal-id><journal-title-group><journal-title>Human mutation</journal-title></journal-title-group><issn pub-type="ppub">1059-7794</issn><issn pub-type="epub">1098-1004</issn></journal-meta><article-meta><article-id pub-id-type="pmid">22949387</article-id><article-id pub-id-type="pmc">4318556</article-id><article-id pub-id-type="doi">10.1002/humu.22214</article-id><article-id pub-id-type="manuscript">NIHMS525444</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Calibration of Multiple In Silico Tools for Predicting Pathogenicity of Mismatch Repair Gene Missense Substitutions</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Thompson</surname><given-names>Bryony A.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Greenblatt</surname><given-names>Marc S.</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Vallee</surname><given-names>Maxime P.</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Herkert</surname><given-names>Johanna C.</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Tessereau</surname><given-names>Chloe</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Young</surname><given-names>Erin L.</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Adzhubey</surname><given-names>Ivan A.</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Biao</given-names></name><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Bell</surname><given-names>Russell</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Feng</surname><given-names>Bingjian</given-names></name><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Mooney</surname><given-names>Sean D.</given-names></name><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>Radivojac</surname><given-names>Predrag</given-names></name><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Sunyaev</surname><given-names>Shamil R.</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Frebourg</surname><given-names>Thierry</given-names></name><xref ref-type="aff" rid="A12">12</xref></contrib><contrib contrib-type="author"><name><surname>Hofstra</surname><given-names>Robert M.W.</given-names></name><xref ref-type="aff" rid="A13">13</xref></contrib><contrib contrib-type="author"><name><surname>Sijmons</surname><given-names>Rolf H.</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Boucher</surname><given-names>Ken</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Thomas</surname><given-names>Alun</given-names></name><xref ref-type="aff" rid="A14">14</xref></contrib><contrib contrib-type="author"><name><surname>Goldgar</surname><given-names>David E.</given-names></name><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Spurdle</surname><given-names>Amanda B.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Tavtigian</surname><given-names>Sean V.</given-names></name><xref ref-type="aff" rid="A7">7</xref><xref ref-type="corresp" rid="CR1">*</xref></contrib></contrib-group><aff id="A1"><label>1</label>Queensland Institute of Medical Research, Herston, Brisbane, Australia</aff><aff id="A2"><label>2</label>School of Medicine, University of Queensland, Brisbane, Australia</aff><aff id="A3"><label>3</label>Department of Medicine, University of Vermont, Burlington, Vermont</aff><aff id="A4"><label>4</label>International Agency for Research on Cancer, Lyon, France</aff><aff id="A5"><label>5</label>Department Genetics, University Medical Center Groningen, Groningen, The Netherlands</aff><aff id="A6"><label>6</label>Breast Cancer Genetics—Cancer Research Center of Lyon, UMR INSERM 1052 CNRS 5286, Lyon, France</aff><aff id="A7"><label>7</label>Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah</aff><aff id="A8"><label>8</label>Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts</aff><aff id="A9"><label>9</label>School of Informatics and Computing, Indiana University, Bloomington, Indiana</aff><aff id="A10"><label>10</label>Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah</aff><aff id="A11"><label>11</label>Buck Institute, Novato, California</aff><aff id="A12"><label>12</label>Molecular Genetics of Cancer and Neuropsychiatric Disease, U614 Inserm, Rouen University, Rouen, France</aff><aff id="A13"><label>13</label>Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands</aff><aff id="A14"><label>14</label>Department of Internal Medicine, Division of Genetic Epidemiology, University of Utah School of Medicine, Salt Lake City, Utah</aff><author-notes><corresp id="CR1"><label>*</label>Correspondence to: Sean V. Tavtigian, Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA. <email>sean.tavtigian@hci.utah.edu</email></corresp></author-notes><pub-date pub-type="nihms-submitted"><day>15</day><month>1</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>22</day><month>10</month><year>2012</year></pub-date><pub-date pub-type="ppub"><month>1</month><year>2013</year></pub-date><pub-date pub-type="pmc-release"><day>05</day><month>2</month><year>2015</year></pub-date><volume>34</volume><issue>1</issue><fpage>255</fpage><lpage>265</lpage><pmc-comment>elocation-id from pubmed: 10.1002/humu.22214</pmc-comment>
<permissions><copyright-statement>© 2012 WILEY PERIODICALS, INC.</copyright-statement><copyright-year>2012</copyright-year></permissions><abstract><p id="P1">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], Mut-Pred, 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><kwd-group><kwd>mismatch repair</kwd><kwd>in silico</kwd><kwd>missense substitutions</kwd><kwd>probability of pathogenicity</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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