chr3-36996701-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000249.4(MLH1):c.199G>T(p.Gly67Trp) 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. 12/21 in silico tools predict a damaging 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. G67E) has been classified as Pathogenic.
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.199G>T | p.Gly67Trp | missense_variant | 2/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.199G>T | p.Gly67Trp | missense_variant | 2/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 15, 1999 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 12, 2023 | This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 17510385]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10480359, 9927034, 21642682]. This variant is expected to disrupt protein structure [Myriad internal data]. - |
Lynch syndrome Pathogenic:1
Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Multifactorial likelihood analysis posterior probability >0.99 - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 17, 2019 | The p.G67W pathogenic mutation (also known as c.199G>T), located in coding exon 2 of the MLH1 gene, results from a G to T substitution at nucleotide position 199. The glycine at codon 67 is replaced by tryptophan, an amino acid with highly dissimilar properties. This mutation was identified as homozygous in three siblings with CMMRD from a French family meeting Amsterdam criteria; microsatellite instability was confirmed in normal buccal cells from one of the affected siblings (Wang Q et al. Hum. Genet.;105:79-85; Wang Q et al. Cancer Res. 1999 Jan;59:294-7; Bertholon J et al. Fam. Cancer 2006;5:29-34; Wimmer K et al. Hum. Genet. 2008 Sep;124:105-22; Lavoine N et al. J. Med. Genet. 2015 Nov;52:770-8). The "G67W, 199G>T" alteration showed reduced MMR activity in vitro (7.3%), which was supported by yeast based assays showing no dominant mutator effect (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. 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. This alteration is predicted to be deleterious by Bayesdel in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Of note, this mutation is also designated as "codon 67, GGG>TGG, Gly>Trp" and Gly67Trp in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Mismatch repair cancer syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 15, 1999 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at