Send to

Choose Destination
Nat Genet. 2014 Feb;46(2):107-115. doi: 10.1038/ng.2854. Epub 2013 Dec 22.

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

Collaborators (139)

Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, Bapat B, Bernstein I, Capellá G, den Dunnen JT, du Sart D, Fabre A, Farrell MP, Farrington SM, Frayling IM, Frebourg T, Goldgar DE, Heinen CD, Holinski-Feder E, Kohonen-Corish M, Robinson KL, Leung SY, Martins A, Moller P, Morak M, Nystrom M, Peltomaki P, Pineda M, Qi M, Ramesar R, Rasmussen LJ, Royer-Pokora B, Scott RJ, Sijmons R, Tavtigian SV, Tops CM, Weber T, Wijnen J, Woods MO, Macrae F, Genuardi M, Castillejo A, Sexton A, Chan AK, Viel A, Blanco A, French A, Laner A, Wagner A, van den Ouweland A, Mensenkamp A, Payá A, Betz B, Redeker B, Smith B, Espenschied C, Cummings C, Engel C, Fornes C, Valenzuela C, Alenda C, Buchanan D, Barana D, Konstantinova D, Cairns D, Glaser E, Silva F, Lalloo F, Crucianelli F, Hogervorst F, Casey G, Tomlinson I, Blanco I, Villar IL, Garcia-Planells J, Bigler J, Shia J, Martinez-Lopez J, Gille JJ, Hopper J, Potter J, Soto JL, Kantelinen J, Ellis K, Mann K, Varesco L, Zhang L, Le Marchand L, Marafie MJ, Nordling M, Tibiletti MG, Kahan MA, Ligtenberg M, Clendenning M, Jenkins M, Speevak M, Digweed M, Kloor M, Hitchins M, Myers M, Aronson M, Valentin MD, Kutsche M, Parsons M, Walsh M, Kansikas M, Zahary MN, Pedroni M, Heider N, Poplawski N, Rahner N, Lindor NM, Sala P, Nan P, Propping P, Newcomb P, Sarin R, Haile R, Hofstra R, Ward R, Tricarico R, Bacares R, Young S, Chialina S, Kovalenko S, Gunawardena SR, Moreno S, Ho SL, Yuen ST, Thibodeau SN, Gallinger S, Burnett T, Teitsch T, Chan TL, Smyrk T, Cranston T, Psofaki V, Steinke-Lange V, Barbera VM.

Author information

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
School of Medicine, University of Queensland, Brisbane, Australia.
Department of Colorectal Medicine and Genetics, Royal Melbourne Hospital, Australia.
Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT, USA.
Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan.
Department of Pathology, Faculty of Medicine, Health Sciences Center, Kuwait University, Safat, Kuwait.
Department of Lab Medicine and Pathobiology, University of Toronto, Canada.
Danish HNPCC Registry, Copenhagen, Denmark.
Surgical Gastroenterology Department, Aalborg University Hospital, Aalborg, Denmark.
Hereditary Cancer Program, Catalan Institute of Oncology-IDIBELL, Barcelona, Spain.
Center of Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Molecular Genetics Lab, Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Melbourne, Australia.
INSERM UMR S910, Department of Medical Genetics and Functional Genomics, Marseille, France.
Department of Cancer Genetics, Mater Private Hospital, Dublin, Ireland.
Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Scotland.
Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
Inserm U1079, Faculty of Medicine, Institute for Biomedical Research, University of Rouen, France.
Department of Dermatology, University of Utah Medical School, Salt Lake City, UT, USA.
Huntsman Cancer Institute, Salt Lake City, UT, USA.
Center for Molecular Medicine, UConn Health Center, Farmington, CT, USA.
Neag Comprehensive Cancer Center, UConn Health Center, Farmington, CT, USA.
MGZ - Medizinisch Genetisches Zentrum, Munich, Germany.
Klinikum der Universität München, Campus Innenstadt, Medizinische Klinik und Poliklinik IV, Munich, Germany.
School of Medicine, University of Western Sydney, Sydney, Australia.
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia.
St Vincent's Clinical School, University of NSW, Sydney, Australia.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
Hereditary Gastrointestinal Cancer Genetic Diagnosis Laboratory, Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
Inserm U1079, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France.
Research Group on Inherited Cancer, Department of Medical Genetics, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
Division of Genetics, Department of Biosciences, University of Helsinki, Helsinki, Finland.
Department of Medical Genetics, Haartman Institute, University of Helsinki, Finland.
Center for Genetic and Genomic Medicine, The First Affiliated Hospital of Zhejiang University School of Medicine, James Watson Institute of Genomic Sciences, Beijing Genome Institute, China.
University of Rochester Medical Center, NY, USA.
MRC Human Genetics Research Unit, Division of Human Genetics, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, South Africa.
Center for Healthy Aging, University of Copenhagen, Denmark.
Institute of Human Genetics, University of Düsseldorf, Germany.
Discipline of Medical Genetics, Faculty of Health, University of Newcastle, The Hunter Medical Research Institute, NSW, Australia.
The Division of Molecular Medicine, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, Australia.
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
State University of New York at Downstate, Brooklyn, NY, USA.
Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Italy.
Fiorgen Foundation for Pharmacogenomics, Sesto Fiorentino, Italy.
Contributed equally


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.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center