Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database

Nature Genetics volume 46, pages 107–115 (2014)Cite this article

Subjects

Abstract

The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome–associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overview of the five-tiered InSiGHT classification guidelines.
Figure 2: Outcome of standardized five-tiered InSiGHT classification of constitutional MMR gene variants.
Figure 3: Classifications of all documented unique variants by variant type.
Figure 4: Contribution of microattribution to the classification of variants that are not obviously truncating.
Figure 5: Probabilities of pathogenicity for 481 class 3 missense variants of uncertain effect derived by in silico analysis.

Accession codes

Primary accessions

NCBI Reference Sequence

References

  1. Vasen, H.F. et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut 62, 812–823 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Umar, A. et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J. Natl. Cancer Inst. 96, 261–268 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. van Oers, J.M. et al. PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance. Proc. Natl. Acad. Sci. USA 107, 13384–13389 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Win, A.K. et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J. Natl. Cancer Inst. 104, 1363–1372 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Buerki, N. et al. Evidence for breast cancer as an integral part of Lynch syndrome. Genes Chromosom. Cancer 51, 83–91 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Scott, R.J. et al. Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds. Am. J. Hum. Genet. 68, 118–127 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Grindedal, E.M. et al. Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer Epidemiol. Biomarkers Prev. 18, 2460–2467 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Win, A.K. et al. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J. Clin. Oncol. 30, 958–964 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Järvinen, H.J. et al. Ten years after mutation testing for Lynch syndrome: cancer incidence and outcome in mutation-positive and mutation-negative family members. J. Clin. Oncol. 27, 4793–4797 (2009).

    Article  PubMed  Google Scholar 

  10. Plon, S.E. et al. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum. Mutat. 29, 1282–1291 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tavtigian, S.V., Greenblatt, M.S., Goldgar, D.E. & Boffetta, P. Assessing pathogenicity: overview of results from the IARC Unclassified Genetic Variants Working Group. Hum. Mutat. 29, 1261–1264 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Richards, C.S. et al. ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet. Med. 10, 294–300 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Easton, D.F. et al. 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. 81, 873–883 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Goldgar, D.E. et al. Genetic evidence and integration of various data sources for classifying uncertain variants into a single model. Hum. Mutat. 29, 1265–1272 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Goldgar, D.E. et al. Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. Am. J. Hum. Genet. 75, 535–544 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Thompson, B.A. et al. 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. 34, 200–209 (2013).

    Article  CAS  PubMed  Google Scholar 

  17. Spurdle, A.B., Couch, F.J., Hogervorst, F.B., Radice, P. & Sinilnikova, O.M. Prediction and assessment of splicing alterations: implications for clinical testing. Hum. Mutat. 29, 1304–1313 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Greenblatt, M.S. et al. Locus-specific databases and recommendations to strengthen their contribution to the classification of variants in cancer susceptibility genes. Hum. Mutat. 29, 1273–1281 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Plazzer, J.P. et al. The InSiGHT database: utilizing 100 years of insights into Lynch syndrome. Fam. Cancer 12, 175–180 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Peltomäki, P. & Vasen, H. Mutations associated with HNPCC predisposition—update of ICG-HNPCC/INSiGHT mutation database. Dis. Markers 20, 269–276 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Peltomäki, P. & Vasen, H.F. Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 113, 1146–1158 (1997).

    Article  PubMed  Google Scholar 

  22. Ou, J. et al. Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes. Hum. Mutat. 28, 1047–1054 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Woods, M.O. et al. A new variant database for mismatch repair genes associated with Lynch syndrome. Hum. Mutat. 28, 669–673 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Giardine, B. et al. Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach. Nat. Genet. 43, 295–301 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Fox, B.I. et al. Developing an expert panel process to refine health outcome definitions in observational data. J. Biomed. Inform. 46, 795–804 (2013).

    Article  PubMed  Google Scholar 

  26. Kohonen-Corish, M.R. et al. Deciphering the colon cancer genes—report of the InSiGHT–Human Variome Project Workshop, UNESCO, Paris 2010. Hum. Mutat. 32, 491–494 (2011).

    Article  PubMed  Google Scholar 

  27. Thompson, D., Easton, D.F. & Goldgar, D.E. A full-likelihood method for the evaluation of causality of sequence variants from family data. Am. J. Hum. Genet. 73, 652–655 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Senter, L. et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 135, 419–428 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Baglietto, L. et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J. Natl. Cancer Inst. 102, 193–201 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bonadona, V. et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. J. Am. Med. Assoc. 305, 2304–2310 (2011).

    Article  CAS  Google Scholar 

  31. Mangold, E. et al. Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. Int. J. Cancer 116, 692–702 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Barnetson, R.A. et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N. Engl. J. Med. 354, 2751–2763 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Patrinos, G.P. et al. Microattribution and nanopublication as means to incentivize the placement of human genome variation data into the public domain. Hum. Mutat. 33, 1503–1512 (2012).

    Article  PubMed  Google Scholar 

  34. Thompson, B.A. et al. Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions. Hum. Mutat. 34, 255–265 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Vallée, M.P. et al. Classification of missense substitutions in the BRCA genes: a database dedicated to Ex-UVs. Hum. Mutat. 33, 22–28 (2012).

    Article  PubMed  CAS  Google Scholar 

  36. Drost, M. et al. A rapid and cell-free assay to test the activity of Lynch syndrome–associated MSH2 and MSH6 missense variants. Hum. Mutat. 33, 488–494 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Heinen, C.D. & Juel Rasmussen, L. Determining the functional significance of mismatch repair gene missense variants using biochemical and cellular assays. Hered. Cancer Clin. Pract. 10, 9 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Couch, F.J. et al. Assessment of functional effects of unclassified genetic variants. Hum. Mutat. 29, 1314–1326 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Rasmussen, L.J. et al. Pathological assessment of mismatch repair gene variants in Lynch syndrome: past, present and future. Hum. Mutat. 33, 1617–1625 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Leenen, C.H. et al. Pitfalls in molecular analysis for mismatch repair deficiency in a family with biallelic PMS2 germline mutations. Clin. Genet. 80, 558–565 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Mead, L.J. et al. Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes. Clin. Cancer Res. 13, 2865–2869 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Plaschke, J. et al. Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. J. Clin. Oncol. 22, 4486–4494 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Wu, Y. et al. Association of hereditary nonpolyposis colorectal cancer–related tumors displaying low microsatellite instability with MSH6 germline mutations. Am. J. Hum. Genet. 65, 1291–1298 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. You, J.F. et al. Tumours with loss of MSH6 expression are MSI-H when screened with a pentaplex of five mononucleotide repeats. Br. J. Cancer 103, 1840–1845 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Spurdle, A.B. et al. BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk. J. Med. Genet. 49, 525–532 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Xie, J. et al. An MLH1 mutation links BACH1/FANCJ to colon cancer, signaling, and insight toward directed therapy. Cancer Prev. Res. (Phila.) 3, 1409–1416 (2010).

    Article  CAS  Google Scholar 

  47. Kosinski, J., Hinrichsen, I., Bujnicki, J.M., Friedhoff, P. & Plotz, G. Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair. Hum. Mutat. 31, 975–982 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Takahashi, M. et al. Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. Cancer Res. 67, 4595–4604 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Hinrichsen, I. et al. Expression defect size among unclassified MLH1 variants determines pathogenicity in Lynch syndrome diagnosis. Clin. Cancer Res. 19, 2432–2441 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Wildeman, M., van Ophuizen, E., den Dunnen, J.T. & Taschner, P.E. Improving sequence variant descriptions in mutation databases and literature using the Mutalyzer sequence variation nomenclature checker. Hum. Mutat. 29, 6–13 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Arnold, S. et al. Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation, and tumor characteristics. Hum. Mutat. 30, 757–770 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Spurdle, A.B. Clinical relevance of rare germline sequence variants in cancer genes: evolution and application of classification models. Curr. Opin. Genet. Dev. 20, 315–323 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Wimmer, K. & Etzler, J. Constitutional mismatch repair–deficiency syndrome: have we so far seen only the tip of an iceberg? Hum. Genet. 124, 105–122 (2008).

    Article  PubMed  Google Scholar 

  54. 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

  55. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

Download references

Acknowledgements

We thank all submitters of data to the InSiGHT database (retrospective and prospective), the Colon Cancer Family Registry and the German Hereditary Non-polyposis Colorectal Cancer Consortium for their contributions of unpublished data, acknowledged formally through microattribution. We would also like to acknowledge L. Marquart for providing statistical advice and T. O'Mara for providing advice and assistance with the statistical package R. We are extremely grateful to the Hicks Foundation (Australia) for inaugural support of InSiGHT database curator J.-P.P. Funding for VIC teleconferences was provided by the Cancer Council of Victoria. B.A.T. is supported by a Cancer Council of Queensland PhD scholarship and by a Queensland Institute of Medical Research PhD Top-Up award. A.B.S. is a National Health and Medical Research Council Senior Research Fellow. The work performed by A.B.S. and B.A.T. was additionally supported by Cancer Australia (1010859). M.G. is supported by a grant from the Tuscan Tumor Institute (ITT). J.-P.P. is currently supported by the Royal Melbourne Hospital Foundation. S.V.T., M.S.G., A.B.S., L.J.R. and R.S. are supported by grant 1R01CA164944 from the National Cancer Institute/US National Institutes of Health (NCI/US NIH). G.C. and M.P. were supported by the Ministerio de Ciencia e Innovación (SAF 12-33636) and by the Fundación Científica de la Asociación Española Contra el Cáncer. A.F. is supported by the French National Cancer Institute and by the Institut National du Cancer (INCa) French MMR Committee. S.M.F. is supported by grants from the Association of International Cancer Research (12-1087) and by the Medical Research Council UK (MR/K018647/1). NHS Wales National Institute for Health and Social Care (NIHSCR) funding was provided to I.M.F. via the Cardiff & Vale University Health Board. D.E.G. is supported by funding from Mayo Specialized Programs of Research Excellence (SPORE) grant P50CA11620106 (principal investigator J. Ingle). C.D.H. is funded by US NIH grant R01 CA115783-02/CA/NCI. E.H.-F. and M.M. are supported by German Cancer Aid (Deutsche Krebshilfe) and by the Wilhelm Sander Foundation. M.K.-C. is funded by Cancer Institute NSW. S.Y.L. is supported by the Hong Kong Cancer Fund. A.M. is supported by the French National Cancer Institute and by the Direction Générale de l'Offre des Soins (INCa/DGOS). The Sigrid Juselius Foundation funds M.N. Funding for P.P. is provided by the European Research Council (FP7-ERC-232635). L.J.R. is funded by Nordea-Fonden. B.R.-P. is supported by German Cancer Aid. M.O.W. was supported by the Canadian Cancer Society Research Institute (grant 18223).

Author information

Author notes

  1. Bryony A Thompson, Amanda B Spurdle and Vasiliki Psofaki: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    Bryony A Thompson, Amanda B Spurdle & Michael Parsons

  2. School of Medicine, University of Queensland, Brisbane, Queensland, Australia

    Bryony A Thompson

  3. Department of Colorectal Medicine and Genetics, Royal Melbourne Hospital, Melbourne, Victoria, Australia

    John-Paul Plazzer & Finlay Macrae

  4. Vermont Cancer Center, University of Vermont College of Medicine, Burlington, Vermont, USA

    Marc S Greenblatt

  5. Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan

    Kiwamu Akagi

  6. Department of Pathology, Faculty of Medicine, Health Sciences Center, Kuwait University, Safat, Kuwait

    Fahd Al-Mulla

  7. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    Bharati Bapat

  8. Danish Hereditary Non-polyposis Colorectal Cancer Registry, Copenhagen, Denmark

    Inge Bernstein

  9. Department of Surgical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark

    Inge Bernstein

  10. Hereditary Cancer Program, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain

    Gabriel Capellá, Marta Pineda & Ignacio Blanco

  11. Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands

    Johan T den Dunnen, Carli M Tops & Juul Wijnen

  12. Molecular Genetics Laboratory, Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia

    Desiree du Sart

  13. Department of Medical Genetics and Functional Genomics, INSERM UMR S910, Marseille, France

    Aurelie Fabre

  14. Department of Cancer Genetics, Mater Private Hospital, Dublin, Ireland

    Michael P Farrell

  15. Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

    Susan M Farrington

  16. Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK

    Ian M Frayling

  17. INSERM U1079, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France

    Thierry Frebourg & Alexandra Martins

  18. Department of Genetics, Rouen University Hospital, Rouen, France

    Thierry Frebourg

  19. Department of Dermatology, University of Utah Medical School, Salt Lake City, Utah, USA

    David E Goldgar

  20. Huntsman Cancer Institute, Salt Lake City, Utah, USA

    David E Goldgar & Sean V Tavtigian

  21. Center for Molecular Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA

    Christopher D Heinen

  22. Neag Comprehensive Cancer Center, University of Connecticut Health Center, Farmington, Connecticut, USA

    Christopher D Heinen & Andreas Laner

  23. Medizinisch Genetisches Zentrum (MGZ), Munich, Germany

    Elke Holinski-Feder & Monika Morak

  24. Klinikum der Universität München, Campus Innenstadt, Medizinische Klinik und Poliklinik IV, Munich, Germany

    Elke Holinski-Feder & Monika Morak

  25. Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

    Maija Kohonen-Corish

  26. School of Medicine, University of Western Sydney, Sydney, New South Wales, Australia

    Maija Kohonen-Corish

  27. St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia

    Maija Kohonen-Corish

  28. Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    Kristina Lagerstedt Robinson

  29. Department of Pathology, Hereditary Gastrointestinal Cancer Genetic Diagnosis Laboratory, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong

    Suet Yi Leung, Anthony K W Chan, Siu Lun Ho, Siu Tsan Yuen & Tsun Leung Chan

  30. Department of Medical Genetics, Research Group on Inherited Cancer, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway

    Pal Moller

  31. Department of Biosciences, Division of Genetics, University of Helsinki, Helsinki, Finland

    Minna Nystrom, Jukka Kantelinen & Minttu Kansikas

  32. Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland

    Paivi Peltomaki

  33. Center for Genetic and Genomic Medicine, First Affiliated Hospital of Zhejiang University School of Medicine, James Watson Institute of Genomic Sciences, Beijing Genome Institute, Beijing, China

    Ming Qi

  34. School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, USA

    Ming Qi

  35. Division of Human Genetics, Medical Research Council (MRC) Human Genetics Research Unit, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

    Rajkumar Ramesar

  36. Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark

    Lene Juel Rasmussen

  37. Institute of Human Genetics, University of Düsseldorf, Düsseldorf, Germany

    Brigitte Royer-Pokora, Beate Betz, Nils Rahner & Verena Steinke-Lange

  38. Discipline of Medical Genetics, Faculty of Health, University of Newcastle, Hunter Medical Research Institute, Newcastle, New South Wales, Australia

    Rodney J Scott

  39. Division of Molecular Medicine, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales, Australia

    Rodney J Scott

  40. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Rolf Sijmons

  41. Department of Surgery, State University of New York Downstate, Brooklyn, New York, USA

    Thomas Weber

  42. Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada

    Michael O Woods

  43. Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy

    Maurizio Genuardi

  44. Fiorgen Foundation for Pharmacogenomics, Sesto Fiorentino, Florence, Italy

    Maurizio Genuardi, Francesca Crucianelli & Rossella Tricarico

  45. Department of Molecular Genetics, Elche University General Hospital, Elche, Spain

    Adela Castillejo & José Luis Soto

  46. Familial Cancer Centre, Royal Melbourne Hospital, Melbourne, Victoria, Australia

    Adrienne Sexton & Kirsty Mann

  47. Oncological Referral Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy

    Alessandra Viel

  48. Hereditary Gastrointestinal Cancer Prevention Program, University of California, San Francisco, San Francisco, California, USA

    Amie Blanco & Megan Myers

  49. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA

    Amy French, Shanaka R Gunawardena, Stephen N Thibodeau & Tom Smyrk

  50. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands

    Anja Wagner, Ans van den Ouweland & Robert Hofstra

  51. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands

    Arjen Mensenkamp & Marjolijn Ligtenberg

  52. Department of Pathology, Hospital Universitario Alicante, Alicante, Spain

    Artemio Payá & Cristina Alenda

  53. Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands

    Bert Redeker

  54. Benefis Sletten Cancer Institute, Great Falls, Montana, USA

    Betsy Smith

  55. Division of Clinical Cancer Genetics, City of Hope, Duarte, California, USA

    Carin Espenschied

  56. Family Cancer Clinic, St. Mark's Hospital, Harrow, UK

    Carole Cummings

  57. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany

    Christoph Engel

  58. Histocompatibility and Molecular Biology Laboratory, Italian Hospital Garibaldi, Rosario Santa Fe, Argentina

    Claudia Fornes & Sergio Chialina

  59. School of Medicine, New York University, New York, New York, USA

    Cristian Valenzuela

  60. Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    Daniel Buchanan, Mark Clendenning & Michael Walsh

  61. Department of Medical Oncology, Health District 5 West Vicenza, Hospital of Montecchio Maggiore, Montecchio Maggiore (VI), Italy

    Daniela Barana

  62. Molecular Medicine Center, Medical University of Sofia, Sofia, Bulgaria

    Darina Konstantinova

  63. Merseyside and Cheshire Regional Molecular Genetics Laboratory, Liverpool Women's Hospital, Liverpool, UK

    Dianne Cairns

  64. International Society for Gastrointestinal Hereditary Tumours,

    Elizabeth Glaser

  65. Laboratory of Genomics and Molecular Biology, A.C. Camargo Cancer Center, São Paulo, Brazil

    Felipe Silva

  66. Manchester Centre for Genomic Medicine, Central Manchester University Hospitals National Health Service (NHS) Foundation Trust, Manchester, UK

    Fiona Lalloo

  67. Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Frans Hogervorst

  68. Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Frans Hogervorst

  69. Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA

    Graham Casey & Robert Haile

  70. Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London, UK

    Ian Tomlinson

  71. Department of Molecular Biology, 12 de Octubre University Hospital, Madrid, Spain

    Isabel López Villar

  72. Institute of Genomic Medicine, University of Valencia, Valencia, Spain

    Javier Garcia-Planells

  73. Medical Sciences, Amgen, Inc., Seattle, Washington, USA

    Jeanette Bigler

  74. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Jinru Shia & Ruben Bacares

  75. Molecular Biology Laboratory, 12 de Octubre University Hospital, Madrid, Spain

    Joaquin Martinez-Lopez

  76. Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands

    Johan J P Gille

  77. Centre for Molecular Environmental, Genetic and Analytic (MEGA) Epidemiology, University of Melbourne, Melbourne, Victoria, Australia

    John Hopper & Mark Jenkins

  78. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    John Potter & Polly Newcomb

  79. Hunter Family Cancer Service, Waratah, New South Wales, Australia

    Kate Ellis

  80. Center for Hereditary Tumours, National Institute for Cancer Research, Genoa, Italy

    Liliana Varesco

  81. Diagnostic Molecular Genetics Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Liying Zhang

  82. University of Hawaii Cancer Center, Honolulu, Hawaii, USA

    Loic Le Marchand & Terrilea Burnett

  83. Cancer Genetics Unit, Kuwait Medical Genetics Centre, Kuwait City, Kuwait

    Makia J Marafie

  84. Department of Molecular and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Margareta Nordling

  85. Unit of Pathology, Varese Hospital, Varese, Italy

    Maria Grazia Tibiletti

  86. Molecular Oncology Institute of Basic Sciences and Experimental Medicine (ICBME), Hospital Italiano de Buenos Aires, Buenose Aires, Argentina

    Mariano Ariel Kahan

  87. Division of Genetics, Trillium Health Partners, Credit Valley Hospital, Mississauga, Ontario, Canada

    Marsha Speevak

  88. Department of Human Genetics, Institute of Medical Genetics and Human Genetics, Charité–Universitätsmedizin Berlin, Berlin, Germany

    Martin Digweed

  89. Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany

    Matthias Kloor

  90. Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydeny, New South Wales, Australia

    Megan Hitchins & Robyn Ward

  91. Familial Gastrointestinal Cancers Unit, Mount Sinai Hospital, Toronto, Ontario, Canada

    Melyssa Aronson

  92. Department of Oncology, Clinical Science, Lund University, Lund, Sweden

    Mev Dominguez Valentin

  93. Laboratory for Molecular Medicine, Praenatalzentrum Laboratories, Hamburg, Germany

    Michael Kutsche

  94. Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Pulau Penang, Malaysia

    Mohd Nizam Zahary

  95. Department of Medicine and Medical Specialties, Modena University Hospital, Modena, Italy

    Monica Pedroni

  96. RIKEN Genomic Sciences Center, Yokohama, Japan

    Nao Heider

  97. South Australia Pathology, Women's and Children's Hospital, Adelaide, South Australia, Australia

    Nicola Poplawski

  98. Department of Health Science Research, Mayo Clinic, Scottsdale, Arizona, USA

    Noralane M Lindor

  99. Hereditary Cancers of the Digestive Tract Unit, Predictive and Preventive Medicine, National Tumor Institute IRCCS Foundation, Milan, Italy

    Paola Sala

  100. School of Life Sciences, Fudan University, Shanghai, China

    Peng Nan

  101. Institute of Human Genetics, University of Bonn, Bonn, Germany

    Peter Propping

  102. Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Mumbai, India

    Rajiv Sarin

  103. Cancer Genetics Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

    Sean Young

  104. Genetic Technologies, Ltd., Melbourne, Victoria, Australia

    Serguei Kovalenko

  105. Genetics Service, Hospital Virgen del Camino, Camino, Spain

    Sira Moreno

  106. Zane Cohen Centre for Digestive Diseases, Toronto, Ontario, Canada

    Steve Gallinger

  107. Bioinformatics, Dartmouth Medical School, Dartmouth College, Lebanon, New Hampshire, USA

    Therese Teitsch

  108. Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, UK

    Treena Cranston

  109. Biochemical Laboratory, University Hospital of Ioannina, Ioannina, Greece

    Vasiliki Psofaki

  110. Research Laboratory, University Hospital of Elche, Elche, Spain

    Victor-Manuel Barbera

Authors
  1. Bryony A Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amanda B Spurdle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John-Paul Plazzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marc S Greenblatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kiwamu Akagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fahd Al-Mulla
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bharati Bapat
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Inge Bernstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gabriel Capellá
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Johan T den Dunnen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Desiree du Sart
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Aurelie Fabre
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Michael P Farrell
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Susan M Farrington
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ian M Frayling
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Thierry Frebourg
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. David E Goldgar
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Christopher D Heinen
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Elke Holinski-Feder
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Maija Kohonen-Corish
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Kristina Lagerstedt Robinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Suet Yi Leung
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Alexandra Martins
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Pal Moller
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Monika Morak
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Minna Nystrom
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Paivi Peltomaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Marta Pineda
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Ming Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Rajkumar Ramesar
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Lene Juel Rasmussen
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Brigitte Royer-Pokora
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. Rodney J Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. Rolf Sijmons
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. Sean V Tavtigian
    View author publications

    You can also search for this author in PubMed Google Scholar

  36. Carli M Tops
    View author publications

    You can also search for this author in PubMed Google Scholar

  37. Thomas Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

  38. Juul Wijnen
    View author publications

    You can also search for this author in PubMed Google Scholar

  39. Michael O Woods
    View author publications

    You can also search for this author in PubMed Google Scholar

  40. Finlay Macrae
    View author publications

    You can also search for this author in PubMed Google Scholar

  41. Maurizio Genuardi
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

on behalf of InSiGHT

  • The InSiGHT collaborators are as follows:

    • Adela Castillejo
    • , Adrienne Sexton
    • , Anthony K W Chan
    • , Alessandra Viel
    • , Amie Blanco
    • , Amy French
    • , Andreas Laner
    • , Anja Wagner
    • , Ans van den Ouweland
    • , Arjen Mensenkamp
    • , Artemio Payá
    • , Beate Betz
    • , Bert Redeker
    • , Betsy Smith
    • , Carin Espenschied
    • , Carole Cummings
    • , Christoph Engel
    • , Claudia Fornes
    • , Cristian Valenzuela
    • , Cristina Alenda
    • , Daniel Buchanan
    • , Daniela Barana
    • , Darina Konstantinova
    • , Dianne Cairns
    • , Elizabeth Glaser
    • , Felipe Silva
    • , Fiona Lalloo
    • , Francesca Crucianelli
    • , Frans Hogervorst
    • , Graham Casey
    • , Ian Tomlinson
    • , Ignacio Blanco
    • , Isabel López Villar
    • , Javier Garcia-Planells
    • , Jeanette Bigler
    • , Jinru Shia
    • , Joaquin Martinez-Lopez
    • , Johan J P Gille
    • , John Hopper
    • , John Potter
    • , José Luis Soto
    • , Jukka Kantelinen
    • , Kate Ellis
    • , Kirsty Mann
    • , Liliana Varesco
    • , Liying Zhang
    • , Loic Le Marchand
    • , Makia J Marafie
    • , Margareta Nordling
    • , Maria Grazia Tibiletti
    • , Mariano Ariel Kahan
    • , Marjolijn Ligtenberg
    • , Mark Clendenning
    • , Mark Jenkins
    • , Marsha Speevak
    • , Martin Digweed
    • , Matthias Kloor
    • , Megan Hitchins
    • , Megan Myers
    • , Melyssa Aronson
    • , Mev Dominguez Valentin
    • , Michael Kutsche
    • , Michael Parsons
    • , Michael Walsh
    • , Minttu Kansikas
    • , Mohd Nizam Zahary
    • , Monica Pedroni
    • , Nao Heider
    • , Nicola Poplawski
    • , Nils Rahner
    • , Noralane M Lindor
    • , Paola Sala
    • , Peng Nan
    • , Peter Propping
    • , Polly Newcomb
    • , Rajiv Sarin
    • , Robert Haile
    • , Robert Hofstra
    • , Robyn Ward
    • , Rossella Tricarico
    • , Ruben Bacares
    • , Sean Young
    • , Sergio Chialina
    • , Serguei Kovalenko
    • , Shanaka R Gunawardena
    • , Sira Moreno
    • , Siu Lun Ho
    • , Siu Tsan Yuen
    • , Stephen N Thibodeau
    • , Steve Gallinger
    • , Terrilea Burnett
    • , Therese Teitsch
    • , Tsun Leung Chan
    • , Tom Smyrk
    • , Treena Cranston
    • , Vasiliki Psofaki
    • , Verena Steinke-Lange
    •  & Victor-Manuel Barbera

Contributions

A.B.S. and B.A.T. drafted the manuscript. B.A.T. conducted InSiGHT database nomenclature standardization and data cleaning, systematic literature and data review, statistical analyses and final data analyses and assisted in the presentation of data in web-based format. B.A.T., A.B.S., S.V.T., M.S.G., D.E.G. and M.G. formulated the baseline guidelines for consideration by VIC members. B.A.T. and A.B.S. developed the functional flowchart and, with L.J.R., C.D.H., G.C., M.P., A.M., B.R.-P., E.H.-F., M.S.G., M.M., T.F. and M.N. formed the functional subcommittee contributing to the supporting documents for functional assay interpretation. D.E.G. provided statistical input. J.-P.P. provided data management, organized teleconferences, collated information after teleconferences, coordinated microattribution and was responsible for the presentation of data in web-based format. J.T.d.D. provided support for the LOVD database and created the LOVD nanopublications. F.M. is the responsible InSiGHT Councilor who initiated the concept of VIC in 2007 and has been responsible for advocating for funding and organizing the face-to-face meeting in Paris. M.G. coordinated VIC and chaired teleconferences and face-to-face meetings. B.A.T., A.B.S., S.V.T., M.S.G., D.E.G., M.G., F.M., L.J.R., C.D.H., G.C., M.P., A.M., B.R.-P., E.H.-F., M.S.G., M.M., T.F., M.N., K.A., F.A.-M., B.B., I.B., D.d.S., A.F., M.P.F., S.M.F., I.M.F., M.K.-C., K.L.R., S.Y.L., P.M., P.P., M.Q., R.R., R.J.S., R.S., C.M.T., T.W., J.W. and M.O.W. provided critique of the classification criteria and/or participated in review of variants at teleconferences or face-to-face meetings or by e-mail and provided critical review of the manuscript.

Corresponding author

Correspondence to Maurizio Genuardi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

A full list of collaborators assigned microattributions for this study appears at the end of the paper with affiliations.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1 and 2, and Supplementary Tables 2–7 and 9 (PDF 4174 kb)

Supplementary Table 1

Details of non-constitutional variants on the InSiGHT database (XLSX 31 kb)

Supplementary Table 8

Summary justifications for class 4: likely pathogenic and class 5: pathogenic “not obviously truncating” nonsynonymous variants classified by the InSiGHT Variant Interpretation Committee (XLSX 67 kb)

Source data

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Thompson, B., Spurdle, A., Plazzer, JP. et al. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet 46, 107–115 (2014). https://doi.org/10.1038/ng.2854

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2854

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing