1 Aalborg University Hospital, The Faculty of Medicine, Aalborg University, VBN2 The Faculty of Medicine, Aalborg University, VBN3 Mave- Tarmkirurgi, The Faculty of Medicine, Aalborg University, VBN4 Klinik Medicin, The Faculty of Medicine, Aalborg University, VBN5 1] Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.  School of Medicine, University of Queensland, Brisbane, Queensland, Australia. .6 1] Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. .7 Royal Melbourne Hospital8 Vermont Cancer Center, University of Vermont College of Medicine, Burlington, Vermont, USA.9 Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan.10 Department of Pathology, Faculty of Medicine, Health Sciences Center, Kuwait University, Safat, Kuwait.11 University of Toronto12 Hereditary Cancer Program, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain.13 Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.14 Molecular Genetics Laboratory, Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.15 INSERM UMR S910, Department of Medical Genetics and Functional Genomics, Marseille, France.16 Department of Cancer Genetics, Mater Private Hospital, Dublin, Ireland.17 Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.18 University Hospital of Wales19 1] INSERM U1079, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France.  Department of Genetics, Rouen University Hospital, Rouen, France.20 1] Department of Dermatology, University of Utah Medical School, Salt Lake City, Utah, USA.  Huntsman Cancer Institute, Salt Lake City, Utah, USA.21 1] Center for Molecular Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA.  Neag Comprehensive Cancer Center, University of Connecticut Health Center, Farmington, Connecticut, USA.22 1] Medizinisch Genetisches Zentrum (MGZ), Munich, Germany.  Klinikum der Universität München, Campus Innenstadt, Medizinische Klinik und Poliklinik IV, Munich, Germany.23 1] Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.  School of Medicine, University of Western Sydney, Sydney, New South Wales, Australia.  St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia.24 Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.25 Hereditary Gastrointestinal Cancer Genetic Diagnosis Laboratory, Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.26 INSERM U1079, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France.27 Research Group on Inherited Cancer, Department of Medical Genetics, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway.28 Department of Biosciences, Division of Genetics, University of Helsinki, Helsinki, Finland.29 Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.30 1] 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.  School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, USA.31 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.32 Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark.33 Institute of Human Genetics, University of Düsseldorf, Düsseldorf, Germany.34 1] Discipline of Medical Genetics, Faculty of Health, University of Newcastle, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.  Division of Molecular Medicine, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales, Australia.35 Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.36 Huntsman Cancer Institute, Salt Lake City, Utah, USA.37 Department of Surgery, State University of New York Downstate, Brooklyn, New York, USA.38 Memorial University of Newfoundland39 1] Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.  Fiorgen Foundation for Pharmacogenomics, Sesto Fiorentino, Florence, Italy.40 Department of Molecular Genetics, Elche University General Hospital, Elche, Spain.41 Istituto di Ricovero e Cura a Carattere Scientifico IRCCS42 Hereditary Gastrointestinal Cancer Prevention Program, University of California, San Francisco, San Francisco, California, USA.43 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.44 Neag Comprehensive Cancer Center, University of Connecticut Health Center, Farmington, Connecticut, USA.45 Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.46 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.47 Department of Pathology, Hospital Universitario Alicante, Alicante, Spain.48 Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.49 Benefis Sletten Cancer Institute, Great Falls, Montana, USA.50 Division of Clinical Cancer Genetics, City of Hope, Duarte, California, USA.51 Family Cancer Clinic, St. Mark's Hospital, Harrow, UK.52 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.53 Histocompatibility and Molecular Biology Laboratory, Italian Hospital Garibaldi, Rosario Santa Fe, Argentina.54 School of Medicine, New York University, New York, New York, USA.55 Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.56 Department of Medical Oncology, Health District 5 West Vicenza, Hospital of Montecchio Maggiore, Montecchio Maggiore (VI), Italy.57 University of Sofia58 Merseyside and Cheshire Regional Molecular Genetics Laboratory, Liverpool Women's Hospital, Liverpool, UK.59 International Society for Gastrointestinal Hereditary Tumours.60 Laboratory of Genomics and Molecular Biology, A.C. Camargo Cancer Center, São Paulo, Brazil.61 Manchester Centre for Genomic Medicine, Central Manchester University Hospitals National Health Service (NHS) Foundation Trust, Manchester, UK.62 Fiorgen Foundation for Pharmacogenomics, Sesto Fiorentino, Florence, Italy.63 1] Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands.  Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.64 Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA.65 Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London, UK.66 Department of Molecular Biology, 12 de Octubre University Hospital, Madrid, Spain.67 Institute of Genomic Medicine, University of Valencia, Valencia, Spain.68 Medical Sciences, Amgen, Inc., Seattle, Washington, USA.69 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.70 Molecular Biology Laboratory, 12 de Octubre University Hospital, Madrid, Spain.71 Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.72 Centre for Molecular Environmental, Genetic and Analytic (MEGA) Epidemiology, University of Melbourne, Melbourne, Victoria, Australia.73 Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.74 Hunter Family Cancer Service, Waratah, New South Wales, Australia.75 Center for Hereditary Tumours, National Institute for Cancer Research, Genoa, Italy.76 Diagnostic Molecular Genetics Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.77 University of Hawaii Cancer Center, Honolulu, Hawaii, USA.78 Cancer Genetics Unit, Kuwait Medical Genetics Centre, Kuwait City, Kuwait.79 Department of Molecular and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.80 Unit of Pathology, Varese Hospital, Varese, Italy.81 Hospital Italiano de Buenos Aires82 Division of Genetics, Trillium Health Partners, Credit Valley Hospital, Mississauga, Ontario, Canada.83 Department of Human Genetics, Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.84 Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.85 Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydeny, New South Wales, Australia.86 Familial Gastrointestinal Cancers Unit, Mount Sinai Hospital, Toronto, Ontario, Canada.87 Department of Oncology, Clinical Science, Lund University, Lund, Sweden.88 Laboratory for Molecular Medicine, Praenatalzentrum Laboratories, Hamburg, Germany.89 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.90 Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Pulau Penang, Malaysia.91 Department of Medicine and Medical Specialties, Modena University Hospital, Modena, Italy.92 RIKEN Genomic Sciences Center, Yokohama, Japan.93 Women's and Children's Hospital Adelaide94 Department of Health Science Research, Mayo Clinic, Scottsdale, Arizona, USA.95 Hereditary Cancers of the Digestive Tract Unit, Predictive and Preventive Medicine, National Tumor Institute IRCCS Foundation, Milan, Italy.96 School of Life Sciences, Fudan University, Shanghai, China.97 Institute of Human Genetics, University of Bonn, Bonn, Germany.98 Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Mumbai, India.99 Cancer Genetics Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.100 Genetic Technologies, Ltd., Melbourne, Victoria, Australia.101 Hospital Virgen del Camino102 Zane Cohen Centre for Digestive Diseases, Toronto, Ontario, Canada.103 Bioinformatics, Dartmouth Medical School, Dartmouth College, Lebanon, New Hampshire, USA.104 Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, UK.105 Biochemical Laboratory, University Hospital of Ioannina, Ioannina, Greece.106 Research Laboratory, University Hospital of Elche, Elche, Spain.107 unknown108 Royal Melbourne Hospital109 University of Toronto110 University Hospital of Wales111 Memorial University of Newfoundland112 Istituto di Ricovero e Cura a Carattere Scientifico IRCCS113 University of Sofia114 Hospital Italiano de Buenos Aires115 Women's and Children's Hospital Adelaide116 Hospital Virgen del Camino
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.
Nature Genetics, 2014, Vol 46, Issue 2, p. 107-115