Submissions for variant NM_000249.4(MLH1):c.731G>A (p.Gly244Asp)

dbSNP: rs63750303

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075830	SCV000106844	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Abrogated function, >2 MSI-H tumours, co-segregation with disease & MAF 0.00. Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics	RCV000573119	SCV000673849	pathogenic	Hereditary cancer-predisposing syndrome	2019-05-03	criteria provided, single submitter	clinical testing	The p.G244D pathogenic mutation (also known as c.731G>A), located in coding exon 9 of the MLH1 gene, results from a G to A substitution at nucleotide position 731. The glycine at codon 244 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in numerous individuals with personal and/or family histories consistent with hereditary nonpolyposis colorectal cancer (HNPCC) (Bozzao C et al. Cancer, 2011 Sep;117:4325-35; Casey G et al. JAMA, 2005 Feb;293:799-809; Choi YH et al. Hered Cancer Clin Pract, 2009 Aug;7:14; Pensotti V et al. Genes Chromosomes Cancer, 1997 Jul;19:135-42; Wagner A et al. Am. J. Hum. Genet., 2003 May;72:1088-100). This alteration has also been shown to segregate with disease in three affected individuals (Blasi MF et al. Cancer Res., 2006 Sep;66:9036-44). Furthermore, this alteration has been reported as functionally defective in mismatch repair (Shcherbakova PV et al. Mol. Cell. Biol., 1999 Apr;19:3177-83; Trojan J et al. Gastroenterology, 2002 Jan;122:211-9; Kondo E et al. Cancer Res., 2003 Jun;63:3302-8; Takahashi M et al. Cancer Res., 2007 May;67:4595-604). This alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075830	SCV000919647	pathogenic	Lynch syndrome	2017-09-21	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.731G>A (p.Gly244Asp) variant involves the alteration of a conserved nucleotide that results in a non-conservative amino acid substitution in the N-terminal part of the MLH1 protein which might be involved in protein interactions (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Published functional studies demonstrated that the variant protein virtually lost the ability to bind to its partner proteins (PMS2 or EXO1) and also resulted in a substantially decreased (19.4% of normal) in vitro MMR activity (Kondo 2003, Takahashi 2007). This variant is absent in 246120 control chromosomes. The variant was reported in multiple patients with colorectal cancer and other LS-associated tumors from Lynch syndrome families, including evidence of cosegregation with disease (e.g. Choi 2009, Bozzao 2011, Barrera 2017). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000573119	SCV001349013	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 244 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). Functional studies have shown that this variant disrupts MLH1 binding to PMS2 and EXO1 (PMID: 12810663) and resulted in ~80% reduction in mismatch repair activity (PMID: 17510385). This variant has been reported in over ten individuals affected with Lynch syndrome and colorectal cancer (PMID: 17510385, 21387278). This variant has been shown to segregate with disease in four affected individuals from a Lynch syndrome family (PMID: 29184699). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.730G>C (p.Gly244Arg) and c.731G>T (p.Gly244Val), are also considered to be disease-causing (ClinVar variation ID: 1758254, 90340), suggesting this position is important for the protein function. Based on the available evidence, this variant is classified as Pathogenic.
Invitae	RCV001210008	SCV001381471	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 244 of the MLH1 protein (p.Gly244Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch Syndrome (PMID: 9218993, 12658575, 15713769, 16982745, 21286823). ClinVar contains an entry for this variant (Variation ID: 90339). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MLH1 function (PMID: 10082584, 11781295, 12810663, 16982745, 17510385). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003466961	SCV004193076	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2021-04-06	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354491	SCV001549122	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV001804824	SCV002054097	not provided	Lynch syndrome 1		no assertion provided	literature only