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 Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution.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.

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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Cancer Family Registry and the German Hereditary Non-polyposis Colorectal Cancer Consortium for their contributions of unpublished data, acknowledged formally through microattribution.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

    • Bryony A Thompson
    •  & Amanda B Spurdle

    These authors contributed equally to this work.


  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. INSERM UMR S910, Department of Medical Genetics and Functional Genomics, 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. Hereditary Gastrointestinal Cancer Genetic Diagnosis Laboratory, Department of Pathology, 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. Research Group on Inherited Cancer, Department of Medical Genetics, 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. Medical Research Council (MRC) Human Genetics Research Unit, Division of Human Genetics, 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


  1. on behalf of InSiGHT

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

    The InSiGHT collaborators are as follows:


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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Maurizio Genuardi.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Note, Supplementary Figures 1 and 2, and Supplementary Tables 2–7 and 9

Excel files

  1. 1.

    Supplementary Table 1

    Details of non-constitutional variants on the InSiGHT database

  2. 2.

    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

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