Submissions for variant NM_000249.4(MLH1):c.227T>A (p.Val76Glu)

dbSNP: rs1434599441

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000629926	SCV000750882	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2017-08-29	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. An experimental study showed that this missense change leads to an intermediate mutator phenotype in a yeast model (PMID: 15475387). This variant has not been reported in the literature in individuals with MLH1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with glutamic acid at codon 76 of the MLH1 protein (p.Val76Glu). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glutamic acid.
Ambry Genetics	RCV002448929	SCV002732155	uncertain significance	Hereditary cancer-predisposing syndrome	2020-05-22	criteria provided, single submitter	clinical testing	The p.V76E variant (also known as c.227T>A), located in coding exon 3 of the MLH1 gene, results from a T to A substitution at nucleotide position 227. The valine at codon 76 is replaced by glutamic acid, an amino acid with dissimilar properties. This alteration is identified in an individual whose family history meets Amsterdam criteria; however, the colorectal tumors for two individuals were microsatellite stable (Ambry internal data). This alteration co-segregated with disease in one family (Ambry internal data). In a hybrid yeast-human mutator experiment, this variant demonstrated a substantial loss (>67%) of mismatch repair function (Ellison AR et al. Nucleic Acids Res., 2004 Oct;32:5321-38). 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.
Myriad Genetics, Inc.	RCV003451493	SCV004189430	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-12	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15475387].
All of Us Research Program, National Institutes of Health	RCV004002782	SCV004835257	uncertain significance	Lynch syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glutamic acid at codon 76 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). A functional study has shown that this variant results in a significant decrease in mismatch repair activity (PMID: 15475387). To our knowledge, 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.