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

Thompson BA1, Spurdle AB2, Plazzer JP3, Greenblatt MS4, Akagi K5, Al-Mulla F6, Bapat B7, Bernstein I8, Capellá G9, den Dunnen JT10, du Sart D11, Fabre A12,Farrell MP13, Farrington SM14, Frayling IM15, Frebourg T16, Goldgar DE17, Heinen CD18, Holinski-Feder E19, Kohonen-Corish M20, Robinson KL21, Leung SY22, Martins A23, Moller P24, Morak M19, Nystrom M25, Peltomaki P26, Pineda M9, Qi M27, Ramesar R28, Rasmussen LJ29, Royer-Pokora B30, Scott RJ31,Sijmons R32, Tavtigian SV33, Tops CM10, Weber T34, Wijnen J10, Woods MO35, Macrae F3, Genuardi M36; on behalf of InSiGHT; The InSiGHT collaborators are as follows:, Castillejo A37, Sexton A38, Chan AK22, Viel A39, Blanco A40, French A41, Laner A42, Wagner A43, van den Ouweland A43, Mensenkamp A44, Payá A45, Betz B30, Redeker B46, Smith B47, Espenschied C48, Cummings C49, Engel C50, Fornes C51, Valenzuela C52, Alenda C45, Buchanan D53, Barana D54,Konstantinova D55, Cairns D56, Glaser E57, Silva F58, Lalloo F59, Crucianelli F60, Hogervorst F61, Casey G62, Tomlinson I63, Blanco I9, Villar IL64, Garcia-Planells J65, Bigler J66, Shia J67, Martinez-Lopez J68, Gille JJ69, Hopper J70, Potter J71, Soto JL37, Kantelinen J25, Ellis K72, Mann K38, Varesco L73, Zhang L74, Le Marchand L75, Marafie MJ76, Nordling M77, Tibiletti MG78, Kahan MA79, Ligtenberg M44, Clendenning M53, Jenkins M70, Speevak M80, Digweed M81,Kloor M82, Hitchins M83, Myers M40, Aronson M84, Valentin MD85, Kutsche M86, Parsons M87, Walsh M53, Kansikas M25, Zahary MN88, Pedroni M89, Heider N90, Poplawski N91, Rahner N30, Lindor NM92, Sala P93, Nan P94, Propping P95, Newcomb P71, Sarin R96, Haile R62, Hofstra R43, Ward R83, Tricarico R60,Bacares R67, Young S97, Chialina S51, Kovalenko S98, Gunawardena SR41, Moreno S99, Ho SL22, Yuen ST22, Thibodeau SN41, Gallinger S100, Burnett T75,Teitsch T101, Chan TL22, Smyrk T41, Cranston T102, Psofaki V103, Steinke-Lange V30, Barbera VM104.

Author information

Abstract

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.