1 Section I. Center for Healthy Aging, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 Center for Healthy Ageing, Faculty of Health and Medical Sciences, Københavns Universitet3 Molecular Aging Program, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet4 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.5 Department of Colorectal Medicine and Genetics, Royal Melbourne Hospital, Melbourne, Victoria, Australia.6 Vermont Cancer Center, University of Vermont College of Medicine, Burlington, Vermont, USA.7 Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan.8 Department of Pathology, Faculty of Medicine, Health Sciences Center, Kuwait University, Safat, Kuwait.9 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.10 Section of Surgery and Internal Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet11 Hereditary Cancer Program, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain.12 Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.13 Molecular Genetics Laboratory, Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.14 INSERM UMR S910, Department of Medical Genetics and Functional Genomics, Marseille, France.15 Department of Cancer Genetics, Mater Private Hospital, Dublin, Ireland.16 Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.17 Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.18 Department of Genetics, Rouen University Hospital19 Department of Dermatology, University of Utah Medical School, Salt Lake City, Utah, USA.20 Center for Molecular Medicine, University of Connecticut Health Center21 Medizinisch Genetisches Zentrum (MGZ), Munich22 Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.23 Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.24 Hereditary Gastrointestinal Cancer Genetic Diagnosis Laboratory, Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.25 INSERM U1079, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France.26 Research Group on Inherited Cancer, Department of Medical Genetics, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway.27 Department of Biosciences, Division of Genetics, University of Helsinki, Helsinki, Finland.28 Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.29 School of Medicine and Dentistry, University of Rochester Medical Center30 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.31 Institute of Human Genetics, University of Düsseldorf, Düsseldorf, Germany.32 Discipline of Medical Genetics, Faculty of Health, University of Newcastle, Hunter Medical Research Institute33 Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.34 Huntsman Cancer Institute, Salt Lake City, Utah, USA.35 Department of Surgery, State University of New York Downstate, Brooklyn, New York, USA.36 Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada.37 Fiorgen Foundation for Pharmacogenomics, Sesto Fiorentino, Florence, Italy.38 Department of Molecular Genetics, Elche University General Hospital, Elche, Spain.39 Familial Cancer Centre, Royal Melbourne Hospital, Melbourne, Victoria, Australia.40 Oncological Referral Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy.41 Hereditary Gastrointestinal Cancer Prevention Program, University of California, San Francisco, San Francisco, California, USA.42 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.43 Neag Comprehensive Cancer Center, University of Connecticut Health Center, Farmington, Connecticut, USA.44 Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.45 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.46 Department of Pathology, Hospital Universitario Alicante, Alicante, Spain.47 Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.48 Benefis Sletten Cancer Institute, Great Falls, Montana, USA.49 Division of Clinical Cancer Genetics, City of Hope, Duarte, California, USA.50 Family Cancer Clinic, St. Mark's Hospital, Harrow, UK.51 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.52 Histocompatibility and Molecular Biology Laboratory, Italian Hospital Garibaldi, Rosario Santa Fe, Argentina.53 School of Medicine, New York University, New York, New York, USA.54 Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.55 Department of Medical Oncology, Health District 5 West Vicenza, Hospital of Montecchio Maggiore, Montecchio Maggiore (VI), Italy.56 Molecular Medicine Center, Medical University of Sofia, Sofia, Bulgaria.57 Merseyside and Cheshire Regional Molecular Genetics Laboratory, Liverpool Women's Hospital, Liverpool, UK.58 International Society for Gastrointestinal Hereditary Tumours.59 Laboratory of Genomics and Molecular Biology, A.C. Camargo Cancer Center, São Paulo, Brazil.60 Manchester Centre for Genomic Medicine, Central Manchester University Hospitals National Health Service (NHS) Foundation Trust, Manchester, UK.61 Department of Molecular Pathology, Netherlands Cancer Institute62 Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA.63 Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London, UK.64 Department of Molecular Biology, 12 de Octubre University Hospital, Madrid, Spain.65 Institute of Genomic Medicine, University of Valencia, Valencia, Spain.66 Medical Sciences, Amgen, Inc., Seattle, Washington, USA.67 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.68 Molecular Biology Laboratory, 12 de Octubre University Hospital, Madrid, Spain.69 Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.70 Centre for Molecular Environmental, Genetic and Analytic (MEGA) Epidemiology, University of Melbourne, Melbourne, Victoria, Australia.71 Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.72 Hunter Family Cancer Service, Waratah, New South Wales, Australia.73 Center for Hereditary Tumours, National Institute for Cancer Research, Genoa, Italy.74 Diagnostic Molecular Genetics Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.75 University of Hawaii Cancer Center, Honolulu, Hawaii, USA.76 Cancer Genetics Unit, Kuwait Medical Genetics Centre, Kuwait City, Kuwait.77 Department of Molecular and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.78 Unit of Pathology, Varese Hospital, Varese, Italy.79 Molecular Oncology Institute of Basic Sciences and Experimental Medicine (ICBME), Hospital Italiano de Buenos Aires, Buenose Aires, Argentina.80 Division of Genetics, Trillium Health Partners, Credit Valley Hospital, Mississauga, Ontario, Canada.81 Department of Human Genetics, Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.82 Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.83 Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydeny, New South Wales, Australia.84 Familial Gastrointestinal Cancers Unit, Mount Sinai Hospital, Toronto, Ontario, Canada.85 Department of Oncology, Clinical Science, Lund University, Lund, Sweden.86 Laboratory for Molecular Medicine, Praenatalzentrum Laboratories, Hamburg, Germany.87 Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Pulau Penang, Malaysia.88 Department of Medicine and Medical Specialties, Modena University Hospital, Modena, Italy.89 RIKEN Genomic Sciences Center, Yokohama, Japan.90 South Australia Pathology, Women's and Children's Hospital, Adelaide, South Australia, Australia.91 Department of Health Science Research, Mayo Clinic, Scottsdale, Arizona, USA.92 Hereditary Cancers of the Digestive Tract Unit, Predictive and Preventive Medicine, National Tumor Institute IRCCS Foundation, Milan, Italy.93 School of Life Sciences, Fudan University, Shanghai, China.94 Institute of Human Genetics, University of Bonn, Bonn, Germany.95 Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre96 Cancer Genetics Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.97 Genetic Technologies, Ltd., Melbourne, Victoria, Australia.98 Genetics Service, Hospital Virgen del Camino, Camino, Spain.99 Zane Cohen Centre for Digestive Diseases, Toronto, Ontario, Canada.100 Bioinformatics, Dartmouth Medical School, Dartmouth College, Lebanon, New Hampshire, USA.101 Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, UK.102 Biochemical Laboratory, University Hospital of Ioannina, Ioannina, Greece.103 Research Laboratory, University Hospital of Elche, Elche, Spain.104 unknown105 Section of Surgery and Internal Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet106 Center for Healthy Ageing, Faculty of Health and Medical Sciences, Københavns Universitet
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
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't