Submissions for variant NM_000249.4(MLH1):c.152T>A (p.Val51Asp)

dbSNP: rs1553638767

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001176427	SCV001340404	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-25	criteria provided, single submitter	clinical testing	This missense variant replaces valine with aspartic acid at codon 51 of the MLH1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant causes a significant defect in mismatch repair activity (personal communications with N. de Wind, Leiden University Medical Center and PMID: 30504929). This variant has been reported in an unaffected individual and in this individual's father and paternal grandmother, who are affected with colon, pancreatic, and gastric cancers (PMID: 26380867). This variant has also been reported in an individual affected with Lynch syndrome (PMID: 25430799). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV003449577	SCV004188276	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-11	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function. This variant is expected to disrupt protein structure [Myriad internal data].
Labcorp Genetics (formerly Invitae), Labcorp	RCV003594099	SCV004293448	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-01	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 918697). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects MLH1 function (PMID: 15475387, 26380867; external communication). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function. This missense change has been observed in individual(s) with clinical features of Lynch syndrome and/or colon cancer (PMID: 25430799, 26380867; external communication). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 51 of the MLH1 protein (p.Val51Asp).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998679	SCV005623557	pathogenic	not provided	2024-03-22	criteria provided, single submitter	clinical testing	The MLH1 c.152T>A (p.Val51Asp) variant has been reported in the published literature in individuals with Lynch Syndrome (PMIDs: 25430799 (2015) and 26380867 (2015)). A functional study found that this variant was damaging to protein function (PMID: 15475387 (2004)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249948	SCV001423890	likely pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004726921	SCV005338071	likely pathogenic	MLH1-related disorder	2024-06-13	no assertion criteria provided	clinical testing	The MLH1 c.152T>A variant is predicted to result in the amino acid substitution p.Val51Asp. This variant has been reported in individuals with Lynch syndrome (Goldberg et al. 2015. PubMed ID: 25430799; Altarescu et al. 2015. PubMed ID: 2638086) Experimental studies suggest this variant impacts protein function (Ellison AR et al 2004. PubMed ID: 15475387; Altarescu et al. 2015. PubMed ID: 2638086). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been classified as likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/918697/). This variant is interpreted as likely pathogenic.