Submissions for variant NM_000249.4(MLH1):c.2110G>A (p.Val704Met)

dbSNP: rs587781811

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001229217	SCV001401655	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2020-11-25	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 to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 956419). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 704 of the MLH1 protein (p.Val704Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine.
Genetic Services Laboratory, University of Chicago	RCV001819928	SCV002068043	uncertain significance	not specified	2020-04-20	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MLH1 gene demonstrated a sequence change, c.2110G>A, in exon 19 that results in an amino acid change, p.Val704Met. This sequence change has not been described in population databases (gnomAD, ExAC). While this sequence change has not been reported in patients with MLH1-related disorders, a different amino acid change at the same location, p.Val704Leu, has been described in a suspected Lynch syndrome patient (PMID: 31386297). The p.Val704Met change affects a poorly conserved amino acid residue located in a domain of the MLH1 protein that is not known to be functional. The p.Val704Met substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Val704Met change remains unknown at this time.
Ambry Genetics	RCV002418789	SCV002725238	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-01	criteria provided, single submitter	clinical testing	The p.V704M variant (also known as c.2110G>A), located in coding exon 19 of the MLH1 gene, results from a G to A substitution at nucleotide position 2110. The valine at codon 704 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and methionine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003469402	SCV004192968	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV002418789	SCV004359273	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-21	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 704 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 not been identified 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.