Submissions for variant NM_000249.4(MLH1):c.731G>T (p.Gly244Val)

dbSNP: rs63750303

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000536939	SCV000625189	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-08-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Gly244Asp) has been determined to be likely pathogenic (PMID: 16982745, 17594722). This suggests that the glycine residue is critical for MLH1 protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this missense change results in impaired mismatch repair function in vitro (PMID: 17510385, 30998989, 31697235). This variant has been reported in individuals affected with clinical features of Lynch syndrome (PMID: 21642682, 30998989, Invitae). ClinVar contains an entry for this variant (Variation ID: 90340). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 244 of the MLH1 protein (p.Gly244Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000075831	SCV000887313	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MLH1 NM_000249.3:c.731G>T has a 74.5% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.
Service de Génétique Médicale, Institut Central des Hôpitaux	RCV000075831	SCV000994923	uncertain significance	Lynch syndrome	2019-04-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381380	SCV002668461	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-10-31	criteria provided, single submitter	clinical testing	The p.G244V variant (also known as c.731G>T), located in coding exon 9 of the MLH1 gene, results from a G to T substitution at nucleotide position 731. The glycine at codon 244 is replaced by valine, an amino acid with dissimilar properties. This alteration has been detected in a family meeting Amsterdam II criteria for Lynch syndrome and the tumor of the proband demonstrated high microsatellite instability, but had normal mismatch repair (MMR) protein expression by immunohistochemistry (Ambry internal data). In one study, protein expression levels in cells expressing this variant were determined to be greater than 75% when compared to the wild type level and MMR activity was reduced compared wild type MLH1 in a complementation assay (Takahashi M et al. Cancer Res. 2007 May;67(10):4595604). This variant also demonstrated deficient activity in a methylation tolerance-based functional assay (Bouvet D et al. Gastroenterology, 2019 08;157:421-431). In another study, steady state levels for this variant were reported to be reduced compared to wild type MLH1 and the p.G244V substitution was predicted to result in destabilization relative to wild type MLH1 (Abildgaard AB et al. Elife, 2019 11;8). The equivalent allele in Bacillus subtilis MutL demonstrated reduced MMR activity and expression, but did not confer a dominant negative effect (Bolz NJ et al. J Bacteriol, 2012 Oct;194:5361-7). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data; Wu H et al. Acta Crystallogr F Struct Biol Commun, 2015 Aug;71:981-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV003452764	SCV004187324	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-17	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 30998989, 17510385]. This variant is expected to disrupt protein structure [Myriad internal data].