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Application of a 5-tiered scheme for standardized ... [Nat Genet. 2013] - PubMed - NCBI

Application of a 5-tiered scheme for standardized ... [Nat Genet. 2013] - PubMed - NCBI

 2013 Dec 22. doi: 10.1038/ng.2854. [Epub ahead of print]

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

Thompson BA1Spurdle AB2Plazzer JP3Greenblatt MS4Akagi K5Al-Mulla F6Bapat B7Bernstein I8Capellá G9den Dunnen JT10du Sart D11Fabre A12,Farrell MP13Farrington SM14Frayling IM15Frebourg T16Goldgar DE17Heinen CD18Holinski-Feder E19Kohonen-Corish M20Robinson KL21Leung SY22Martins A23Moller P24Morak M19Nystrom M25Peltomaki P26Pineda M9Qi M27Ramesar R28Rasmussen LJ29Royer-Pokora B30Scott RJ31,Sijmons R32Tavtigian SV33Tops CM10Weber T34Wijnen J10Woods MO35Macrae F3Genuardi M36on behalf of InSiGHTThe InSiGHT collaborators are as follows:Castillejo A37Sexton A38Chan AK22Viel A39Blanco A40French A41Laner A42Wagner A43van den Ouweland A43Mensenkamp A44Payá A45Betz B30Redeker B46Smith B47Espenschied C48Cummings C49Engel C50Fornes C51Valenzuela C52Alenda C45Buchanan D53Barana D54,Konstantinova D55Cairns D56Glaser E57Silva F58Lalloo F59Crucianelli F60Hogervorst F61Casey G62Tomlinson I63Blanco I9Villar IL64Garcia-Planells J65Bigler J66Shia J67Martinez-Lopez J68Gille JJ69Hopper J70Potter J71Soto JL37Kantelinen J25Ellis K72Mann K38Varesco L73Zhang L74Le Marchand L75Marafie MJ76Nordling M77Tibiletti MG78Kahan MA79Ligtenberg M44Clendenning M53Jenkins M70Speevak M80Digweed M81,Kloor M82Hitchins M83Myers M40Aronson M84Valentin MD85Kutsche M86Parsons M87Walsh M53Kansikas M25Zahary MN88Pedroni M89Heider N90Poplawski N91Rahner N30Lindor NM92Sala P93Nan P94Propping P95Newcomb P71Sarin R96Haile R62Hofstra R43Ward R83Tricarico R60,Bacares R67Young S97Chialina S51Kovalenko S98Gunawardena SR41Moreno S99Ho SL22Yuen ST22Thibodeau SN41Gallinger S100Burnett T75,Teitsch T101Chan TL22Smyrk T41Cranston T102Psofaki V103Steinke-Lange V30Barbera VM104.


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.

[PubMed - as supplied by publisher]

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