ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.188A>G (p.Asp63Gly) (rs1064795693)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478087 SCV000571727 likely pathogenic not provided 2016-09-20 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.188A>G at the cDNA level, p.Asp63Gly (D63G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAC>GGC). Although this variant has not, to our knowledge, been published in the literature as pathogenic or benign, another variant at the same residue, MLH1 Asp63Glu, is considered pathogenic by the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT). MLH1 Asp63Glu has been reported to segregate with Lynch syndrome-related cancers in at least one family and has been shown to result in decreased MLH1 protein expression, deficient mismatch repair activity, and decreased nuclear localization of MLH1 and PMS2 (Raevaara 2005, Hardt 2011). MLH1 Asp63Gly 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 Aspartic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Asp63Gly occurs at a position that is conserved across species and is located in the ATPase domain (Raevaara 2005, Hardt 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider MLH1 Asp63Gly to be a likely pathogenic variant.
Ambry Genetics RCV000570212 SCV000673817 likely pathogenic Hereditary cancer-predisposing syndrome 2016-01-19 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,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species

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