Submissions for variant NM_000249.4(MLH1):c.1591G>A (p.Val531Met)

gnomAD frequency: 0.00001  dbSNP: rs764663152

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168065	SCV000218719	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-09-10	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 531 of the MLH1 protein (p.Val531Met). This variant is present in population databases (rs764663152, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 188166). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MLH1 protein function with a positive predictive value of 95%. 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.
Ambry Genetics	RCV000573554	SCV000662072	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-16	criteria provided, single submitter	clinical testing	The p.V531M variant (also known as c.1591G>A), located in coding exon 14 of the MLH1 gene, results from a G to A substitution at nucleotide position 1591. The valine at codon 531 is replaced by methionine, an amino acid with highly similar properties. 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.
Color Diagnostics, LLC DBA Color Health	RCV000573554	SCV000689823	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 531 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 2/251242 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Counsyl	RCV000662490	SCV000784999	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-03-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284165	SCV001469795	uncertain significance	not provided	2024-10-31	criteria provided, single submitter	clinical testing	The MLH1 c.1591G>A (p.Val531Met) variant has not been reported in individuals with MLH1-related conditions in the published literature. The frequency of this variant in the general population, 0.000008 (2/251242 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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, we are unable to determine the clinical significance of this variant.
Myriad Genetics, Inc.	RCV000662490	SCV004018121	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-13	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000662490	SCV004190644	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2024-01-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995604	SCV004843179	uncertain significance	Lynch syndrome	2024-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 531 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 2/251242 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.