biostudies-literatureThompson BACancer Research UKEuropean Research CouncilWorldwide Cancer ResearchMedical Research CouncilNCI NIH HHSWellcome Trust107-115https://www.ebi.ac.uk/biostudies/studies/S-EPMC4294709biostudies-literatureUnknown46(2)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 Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution.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 classifiNature geneticsApplication of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.PMC4294709R01 CA164944U24 CA074794MR/K018647/1U24 CA07478312076U01 CA074783U01 CA074794R01 CA115783-02P50 CA116201090532U01 CA097735UM1 CA167551U01 CA074800U01 CA074799P50CA116201061R01CA164944R01 CA115783U24 CA074800U24 CA074799U24 CA097735MC_PC_U12752719812-1087MC_U127527198232635Martins AGarcia-Planells JParsons MValenzuela CZhang Lvan den Ouweland Aden Dunnen JTBacares RGoldgar DELe Marchand LYuen STPsofaki VNan PHofstra RGunawardena SRTibiletti MGMensenkamp ASexton ASpeevak MTricarico RLeung SYChialina SKohonen-Corish MYoung SCummings CScott RJBernstein IPlazzer JPSilva FSijmons RBapat BPotter JBuchanan DQi MBigler JDigweed MClendenning MFrebourg TKloor MFarrell MPKonstantinova DGallinger SEngel CAl-Mulla Fdu Sart DRoyer-Pokora BWijnen JCasey GJenkins MValentin MDPeltomaki PLindor NMSpurdle ABKovalenko SBetz BRamesar RSmyrk TMann KMoreno SEspenschied CAlenda CZahary MNSarin RTeitsch TBarbera VMCairns DCrucianelli FNewcomb PBurnett TPropping PHeinen CDGille JJHolinski-Feder EPedroni MHeider NMarafie MJTavtigian SVGlaser ERobinson KLLaner AFornes CHaile RWagner AMartinez-Lopez JKansikas MRahner NMoller PChan TLEllis KPaya ASoto JLGreenblatt MSMacrae FTops CMMyers MThibodeau SNBarana DShia JNordling MHitchins MVaresco LKahan MALigtenberg MPineda MWoods MOCapella GFarrington SMHogervorst FTomlinson IRasmussen LJFrayling IMCastillejo AKutsche MWard RNystrom MBlanco ASteinke-Lange VMorak MChan AKHo SLLalloo FBlanco IPoplawski NHopper JSmith BViel AFabre AVillar ILWalsh MFrench ACranston TAkagi KRedeker BAronson MSala PThompson BAWeber TGenuardi MKantelinen JfalseApplication 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 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 classifi2014-01-01T00:00:00Z2014 Feb2026-05-03T07:51:14.905Z2019-03-27T01:43:28ZS-EPMC42947092436281610.1038/ng.2854