ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.200G>A (p.Gly67Glu) (rs63749939)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075482 SCV000106478 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics RCV000132445 SCV000187539 pathogenic Hereditary cancer-predisposing syndrome 2018-04-23 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);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
Invitae RCV000524267 SCV000253790 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-08-22 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 67 of the MLH1 protein (p.Gly67Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals and families affected with Lynch syndrome (PMID: 16807412, 18033691, 19142183), and has been reported to segregate with colorectal cancer in two families (PMID: 18033691). ClinVar contains an entry for this variant (Variation ID: 17106). Experimental studies in yeast have shown that this missense change disrupts mismatch repair (MMR) activity of the MLH1 protein (PMID: 15475387, 19142183). Furthermore, according to a multifactorial likelihood algorithm using genetic, functional, and population frequency data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). A different missense substitution at this codon (p.Gly67Arg) has been determined to be pathogenic (PMID: 19142183, 18337503, 8521398). This suggests that the glycine residue is critical for MLH1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000216147 SCV000279068 pathogenic not provided 2016-11-21 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.200G>A at the cDNA level, p.Gly67Glu (G67E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGG>GAG). This variant has been observed in several Lynch syndrome families meeting Amsterdam criteria, has been reported to segregate with disease, and was absent from controls (Terdiman 2001, Barnetson 2006, Barnetson 2008, Clyne 2009, Yu 2009, Chubb 2015). Tumor studies from many individuals carrying MLH1 Gly67Glu showed microsatellite instability (MSI-H) and/or loss of MLH1 protein expression (Terdiman 2001, Barnetson 2008, Frolova 2015). Yu et al. (2009) and Clyne et al. (2009) report this variant in an individual with an unusual phenotype including a leiomyosarcoma and male breast cancer. Despite normal results from a splicing assay, other studies have demonstrated that MLH1 Gly67Glu has a deleterious effect on mismatch repair protein function with respect to dominant mutator effect and mutation rate (Ellison 2004, Lastella 2006, Clyne 2009). In addition, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic based on their multifactorial likelihood analysis (Thompson 2014).MLH1 Gly67Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Gly67Glu occurs at a position that is conserved across species and is located in the ATPase domain (Raevaara 2005). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider this variant to be pathogenic.
OMIM RCV000018641 SCV000038924 pathogenic Lynch syndrome II 2009-01-27 no assertion criteria provided literature only
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000216147 SCV000691842 pathogenic not provided no assertion criteria provided clinical testing

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