ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.338T>A (p.Val113Asp)

dbSNP: rs63750559
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164616 SCV000215280 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-23 criteria provided, single submitter clinical testing The p.V113D variant (also known as c.338T>A), located in coding exon 4 of the MLH1 gene, results from a T to A substitution at nucleotide position 338. The valine at codon 113 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This alteration has been reported to have no effect on splicing in two studies (Auclair J et al. Hum. Mutat., 2006 Feb;27:145-54; Rhine CL et al. PLoS Genet., 2018 03;14:e1007231). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000547399 SCV000625150 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-01-15 criteria provided, single submitter clinical testing 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. Algorithms developed specifically for the MLH1 gene (PMID: 22290698, 18383312) suggest that this missense change is likely to be deleterious. However, these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in individuals affected with Lynch syndrome in the literature (PMID: 16395668) and in the Universal Mutation Database (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 90172). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with aspartic acid at codon 113 of the MLH1 protein (p.Val113Asp). The valine residue is highly conserved and there is a large physicochemical difference between valine and aspartic acid.
Myriad Genetics, Inc. RCV003451135 SCV004188443 likely pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-19 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 31784484]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16395668].

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