ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.199G>A (p.Gly67Arg) (rs63750206)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128871 SCV000172728 pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Deficient protein function in appropriate functional assay(s)
Color RCV000128871 SCV000911366 pathogenic Hereditary cancer-predisposing syndrome 2017-11-30 criteria provided, single submitter clinical testing
Counsyl RCV000662719 SCV000785473 pathogenic Lynch syndrome II 2017-08-16 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075474 SCV000592337 pathogenic Lynch syndrome 2012-07-09 criteria provided, single submitter clinical testing
GeneDx RCV000202032 SCV000211109 pathogenic not provided 2018-12-20 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.199G>A at the cDNA level, p.Gly67Arg (G67R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>AGG). This variant has been reported in many individuals with Lynch syndrome, segregated with Lynch syndrome-associated cancers, and was absent from healthy controls. Tumor studies from many of these individuals showed microsatellite instability (MSI-H) and loss of MLH1 and/or PMS2 protein expression (Tannergard 1995, Yuan 2004, Alazzouzi 2005, Casey 2005, Halvarsson 2005, Auclair 2006, Ewald 2007, Lagerstedt Robinson 2007, Takahashi 2007, Drost 2010, Hardt 2011, Pastrello 2011). While some functional assays showed intact PMS2 binding and interaction, no effect on splicing, and no effect on MMR-mediated DNA damage response (Casey 2005, Auclair 2006, Lastella 2006, Fan 2007, Avdievich 2008, Tournier 2008, Kansikas 2011, Andersen 2012, Thompson 2013), multiple other in vivo and in vitro analyses demonstrated that this variant has a deleterious effect on protein function with respect to dominant mutator effect, nuclear localization, expression, mutation rate, and mismatch repair activity (Avdievich 2008, Shimodaira 1998, Shcherbakova 1999, Ellison 2001, Raevaara 2005, Blasi 2006, Takahashi 2007, Drost 2010, Kansikas 2011, Andersen 2012, Borras 2013). In addition, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic based on abrogated function, co-segregation with disease and congruent molecular and clinical phenotype reports (Thompson 2014). MLH1 Gly67Arg was not observed in large population cohorts (Lek 2016). This variant is located in the ATP-binding and hydrolysis domain (Raevaara 2005, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider this variant to be pathogenic.
GeneKor MSA RCV000128871 SCV000821734 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075474 SCV000106471 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Abrogated function, >2 MSI-H tumours, co-segregation with disease & MAF 0.00. Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV000524266 SCV000253789 pathogenic Hereditary nonpolyposis colon cancer 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 67 of the MLH1 protein (p.Gly67Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in numerous individuals and families affected with Lynch syndrome related conditions, and there is some evidence of segregation with disease (PMID: 15563510, 17312306, 8521398, 21239990, 12419761, 18383312, 15613555). ClinVar contains an entry for this variant (Variation ID: 89992). Many experimental studies have shown a significant reduction of mismatch repair activity of the mutated protein in both in vitro and in vivo assays, as well as deleterious effects on other aspects of protein function (PMID: 18337503, 11555625, 9697702, 12810663, 16083711, 18094436). Also, based on a multifactorial likelihood algorithm using genetic, in silico, and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000075474 SCV000711428 pathogenic Lynch syndrome 2017-01-11 criteria provided, single submitter clinical testing The p.Gly67Arg variant in MLH1 has been identified in a large number of individu als with Lynch syndrome and segregated with disease in at least 4 affected famil y members in 2 families (Tannergard 1995, Mitchell 2002, Alazzouzi 2005, Lagerst edt Robinson 2007, InSiGHT database: http://chromium.lovd.nl/LOVD2/colon_cancer/ variants.php). This variant was absent from large population studies. Mice carry ing the p.Gly67Arg variant have a strong cancer predisposition phenotype (Avdiev ich 2008). Additionally, this variant has been classified as pathogenic on Sep 5 , 2013 by the ClinGen-approved InSiGHT panel (ClinVar SCV000106471.2). In summar y, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202032 SCV000257081 pathogenic not provided no assertion criteria provided clinical testing
PreventionGenetics RCV000202032 SCV000805964 pathogenic not provided 2018-01-08 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000075474 SCV000266076 pathogenic Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing

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