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

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 appl...

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Detalhes bibliográficos
Autores: Thompson, Bryony A., Spurdle, Amanda B., Plazzer, John-Paul, Greenblatt, Marc S., Akagi, Kiwamu, Al-Mulla, Fahd, Bapat, Bharati, Bernstein, Inge, Capellá, G. (Gabriel), Dunnen, Johan T. den, Sart, Desiree du, Fabre, Aurelie, Farrell, Michael P., Farrington, Susan M., Frayling, Ian M., Frebourg, Thierry, Goldgar, David E., Heinen, Christopher D., Holinski-Feder, Elke, Kohonen-Corish, Maija, Lagerstedt Robinson, Kristina, Leung, Suet Yi, Martins, Alexandra, Møller, Pål, Morak, Monika, Nystrom, Minna, Peltomäki, Päivi, Pineda Riu, Marta, Qi, Ming, Ramesar, Rajkumar, Rasmussen, Lene Juel, Royer-Pokora, Brigitte, Scott, Rodney J., Sijmons, Rolf H., Tavtigian, Sean V., Tops, Carli M., Weber, Thomas, Wijnen, Juul, Woods, Michael O., Macrae, Finlay, Genuardi, Maurizio, InSiGHT
Formato: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2013
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/125962
Acesso em linha:https://hdl.handle.net/2445/125962
Access Level:acceso abierto
Palavra-chave:Malalties hereditàries
Tumors
Càncer colorectal
Genetic diseases
Colorectal cancer
Descrição
Resumo: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 Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution.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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