ClinVar Miner

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

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Total submissions: 3
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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 2014-12-12 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Well-characterized mutation at same position
Invitae RCV001070471 SCV001235703 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-05-01 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 63 of the MLH1 protein (p.Asp63Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 422297). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Asp63 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been observed in individuals with MLH1-related conditions (PMID: 17569143, 16083711, 11948175), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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