rs63750303
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000249.4(MLH1):c.731G>A(p.Gly244Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G244V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.731G>A | p.Gly244Asp | missense_variant | 9/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.731G>A | p.Gly244Asp | missense_variant | 9/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 28
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Lynch syndrome Pathogenic:2
Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Abrogated function, >2 MSI-H tumours, co-segregation with disease & MAF 0.00. Multifactorial likelihood analysis posterior probability >0.99 - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 21, 2017 | 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 28, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 03, 2019 | 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. - |
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 06, 2021 | - - |
not provided Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 20, 2023 | 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. - |
Lynch syndrome 1 Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at