Calibration of Multiple In Silico Tools for Predicting Pathogenicity of Mismatch Repair Gene Missense Substitutions
Open accessAbstract
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.
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Several efforts have evaluated the performance of available prediction software, to compare them to each other and to assess their ability to predict known disease-causing variants.
“Several efforts have evaluated the performance of available prediction software, to compare them to each other and to assess their ability to predict 'known' disease-causing variants. 14-17”
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References 35 · Cited by 95
Research works printed but not linked: 32
- Adzhubei IA Schmidt S Peshkin L Ramensky VE Gerasimova A Bork P Kondrashov AS Sunyaev SR A method and server for predicting damaging missense mutations. Nat Methods 2010 7 248 249 20354512 PMC2855889
- Ali H Olatubosun A Vihinen M Classification of mismatch repair gene missense variants with PON-MMR. Hum Mutat 2012 33 642 650 22290698
- Arnold S Buchanan DD Barker M Jaskowski L Walsh MD Birney G Woods MO Hopper JL Jenkins MA Brown MA Tavtigian SV Goldgar DE Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation, and tumor characteristics. Hum Mutat 2009 30 757 770 19267393 PMC2707453
- Barnetson RA Cartwright N van Vliet A Haq N Drew K Farrington S Williams N Warner J Campbell H Porteous ME Dunlop MG Classification of ambiguous mutations in DNA mismatch repair genes identified in a population-based study of colorectal cancer. Hum Mutat 2008 29 367 374 18033691
- Chan PA Duraisamy S Miller PJ Newell JA McBride C Bond JP Raevaara T Ollila S Nystrom M Grimm AJ Christodoulou J Oetting WS Interpreting missense variants: comparing computational methods in human disease genes CDKN2A, MLH1, MSH2, MECP2, and tyrosinase (TYR). Hum Mutat 2007 28 683 693 17370310
- Chao EC Velasquez JL Witherspoon MS Rozek LS Peel D Ng P Gruber SB Watson P Rennert G Anton-Culver H Lynch H Lipkin SM Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). Hum Mutat 2008 29 852 860 18383312
- Couch FJ Rasmussen LJ Hofstra R Monteiro AN Greenblatt MS de Wind N Assessment of functional effects of unclassified genetic variants. Hum Mutat 2008 29 1314 1326 18951449 PMC2771414
- Easton DF Deffenbaugh AM Pruss D Frye C Wenstrup RJ Allen-Brady K Tavtigian SV Monteiro AN Iversen ES Couch FJ Goldgar DE A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet 2007 81 873 883 17924331 PMC2265654
- Goldgar DE Easton DF Deffenbaugh AM Monteiro AN Tavtigian SV Couch FJ Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. Am J Hum Genet 2004 75 535 544 15290653 PMC1182042
- Greenblatt MS Beaudet JG Gump JR Godin KS Trombley L Koh J Bond JP Detailed computational study of p53 and p16: using evolutionary sequence analysis and disease-associated mutations to predict the functional consequences of allelic variants. Oncogene 2003 22 1150 1163 12606942
- Hicks S Wheeler DA Plon SE Kimmel M Prediction of missense mutation functionality depends on both the algorithm and sequence alignment employed. Hum Mutat 2011 32 661 668 21480434 PMC4154965
- Kohonen-Corish MR Macrae F Genuardi M Aretz S Bapat B Bernstein IT Burn J Cotton RG den Dunnen JT Frebourg T Greenblatt MS Hofstra R Deciphering the colon cancer genes–report of the InSiGHT-Human Variome Project Workshop, UNESCO, Paris 2010. Hum Mutat 2011 32 491 494 21387463
- Kumar P Henikoff S Ng PC Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009 4 1073 1081 19561590
- Li B Krishnan VG Mort ME Xin F Kamati KK Cooper DN Mooney SD Radivojac P Automated inference of molecular mechanisms of disease from amino acid substitutions. Bioinformatics 2009 25 2744 2750 19734154 PMC3140805
- Lynch HT Lynch PM Lanspa SJ Snyder CL Lynch JF Boland CR Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 2009 76 1 18 19659756 PMC2846640
- Miller PJ Duraisamy S Newell JA Chan PA Tie MM Rogers AE Ankuda CK von Walstrom GM Bond JP Greenblatt MS Classifying variants of CDKN2A using computational and laboratory studies. Hum Mutat 2011 32 900 911 21462282
- Ng PC Henikoff S Accounting for human polymorphisms predicted to affect protein function. Genome Res 2002 12 436 446 11875032 PMC155281
- O'Neill SC Rini C Goldsmith RE Valdimarsdottir H Cohen LH Schwartz MD Distress among women receiving uninformative BRCA1/2 results: 12-month outcomes. Psychooncology 2009 18 1088 1096 19214961 PMC3503506
- Pastrello C Pin E Marroni F Bedin C Fornasarig M Tibiletti MG Oliani C Ponz de Leon M Urso ED Della Puppa L Agostini M Viel A Integrated analysis of unclassified variants in mismatch repair genes. Genet Med 2011 13 115 124 21239990
- Plon SE Eccles DM Easton D Foulkes WD Genuardi M Greenblatt MS Hogervorst FB Hoogerbrugge N Spurdle AB Tavtigian SV Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat 2008 29 1282 1291 18951446 PMC3075918
- Reva B Antipin Y Sander C Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res 2011 39 e118 21727090 PMC3177186
- Stone EA Sidow A Physicochemical constraint violation by missense substitutions mediates impairment of protein function and disease severity. Genome Res 2005 15 978 986 15965030 PMC1172042
- Tavtigian SV Byrnes GB Goldgar DE Thomas A Classification of rare mis-sense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications. Hum Mutat 2008a 29 1342 1354 18951461 PMC3938023
- Tavtigian SV Deffenbaugh AM Yin L Judkins T Scholl T Samollow PB de Silva D Zharkikh A Thomas A Comprehensive statistical study of 452 BRCA1 mis-sense substitutions with classification of eight recurrent substitutions as neutral. J Med Genet 2006 43 295 305 16014699 PMC2563222
- Tavtigian SV Greenblatt MS Goldgar DE Boffetta P Assessing pathogenicity: overview of results from the IARC Unclassified Genetic Variants Working Group. Hum Mutat 2008b 29 1261 1264 18951436 PMC2966307
- Thompson BA Goldgar DE Paterson C Clendenning M Walters R Arnold S Parsons MT Walsh MD Gallinger S Haile RW Hopper JL Jenkins MA A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: A report from the colon cancer family registry. Hum Mutat 2012 (in press) PMC3538359 22949379
- Thusberg J Olatubosun A Vihinen M Performance of mutation pathogenicity prediction methods on missense variants. Hum Mutat 2011 32 358 368 21412949
- Vasen HF Watson P Mecklin JP Lynch HT New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999 116 1453 1456 10348829
- Viel A Novella E Genuardi M Capozzi E Fornasarig M Pedroni M Santarosa M De Leon MP Della Puppa L Anti M Boiocchi M Lack of PMS2 gene-truncating mutations in patients with hereditary colorectal cancer. Int J Oncol 1998 13 565 569 9683794
- Wallace IM O'Sullivan O Higgins DG Notredame C M-Coffee: combining multiple sequence alignment methods with T-Coffee. Nucleic Acids Res 2006 34 1692 1699 16556910 PMC1410914
- Wang Q Lasset C Desseigne F Saurin JC Maugard C Navarro C Ruano E Descos L Trillet-Lenoir V Bosset JF Puisieux A Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer. Hum Genet 1999 105 79 85 10480359
- Woods MO Williams P Careen A Edwards L Bartlett S McLaughlin JR Younghusband HB A new variant database for mismatch repair genes associated with Lynch syndrome. Hum Mutat 2007 28 669 673 17347989
- Authors
- Thompson, B. A., Greenblatt, M. S., Vallee, M. P., Herkert, J. C., Tessereau, C., Young, E. L., Adzhubey, I. A., Li, B., Bell, R., Feng, B., Mooney, S. D., Radivojac, P., Sunyaev, S. R., Frebourg, T., Hofstra, R. M. W., Sijmons, R. H., Boucher, K., Thomas, A., Goldgar, D. E., Spurdle, A. B., & Tavtigian, S. V.
- Affiliations
- The University of Queensland (AU)
- University of Vermont (US)
- International Agency for Research on Cancer; Lyon; France
- University Medical Center Groningen (NL)
- Breast Cancer Genetics-Cancer Research Center of Lyon, UMR INSERM 1052 CNRS 5286; Lyon; France
- University of Utah (US)
- Division of Genetics, Brigham and Women's Hospital, Harvard Medical School; Boston; Massachusetts
- Indiana University Bloomington (US)
- Department of Dermatology, University of Utah School of Medicine; Salt Lake City; Utah
- Buck Institute for Research on Aging (US)
- School of Informatics and Computing, Indiana University; Bloomington; Indiana
- Brigham and Women's Hospital (US)
- Molecular Genetics of Cancer and Neuropsychiatric Disease, U614 Inserm, Rouen University; Rouen; France
- Erasmus MC (NL)
- Department of Oncological Sciences, Huntsman Cancer Institute; University of Utah School of Medicine; Salt Lake City; Utah
- QIMR Berghofer Medical Research Institute (AU)
- Corresponding author
- Tavtigian, Sean V.
- ORCID
- Venue
- Human Mutation
- Publisher
- Wiley
- Published
- 2012-10-22
- Volume
- 34
- Issue
- 1
- Pages
- 255-265
- ISSN
- 1059-7794 (ISSN-L)
- PMC
- PMC4318556
- OpenAlex
- W2083022629
- Cited by
- 95
- References
- 35
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 3 · 2022: 6 · 2021: 5 · 2020: 6 · 2019: 9 · 2018: 12 · 2017: 5 · 2016: 6 · 2015: 8 · 2014: 11 · 2013: 13 · 2012: 1
- FWCI
- 6.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Mutation (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Funders
- Cancer Australia (1010859)
- Vrije Universiteit Amsterdam
- National Institutes of Health
- National Health and Medical Research Council (496616)
- Cancer Council Queensland
- National Human Genome Research Institute (U54HG004028)
- National Cancer Institute (CA042014, P30CA042014)
- National Institute of General Medical Sciences (R01GM078598)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- mismatch repair genes, missense substitutions, pathogenicity prediction, in silico prediction tools, instrument calibration, Lynch syndrome, MLH1, MSH2, MSH6, PMS2, MAPP, PolyPhen-2, SIFT, rare variants, variant interpretation
- MeSH terms
- MutL Protein Homolog 1, Mismatch Repair Endonuclease PMS2, Adenosine Triphosphatases, Bayes Theorem, Calibration, Colorectal Neoplasms, Hereditary Nonpolyposis, DNA-Binding Proteins, Humans, Nuclear Proteins, Regression Analysis, Reproducibility of Results, Computational Biology, Genetic Predisposition to Disease, Mutation, Missense, DNA Repair Enzymes, Adaptor Proteins, Signal Transducing, MutS Homolog 2 Protein, DNA Mismatch Repair
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