Submissions for variant NM_000249.4(MLH1):c.544A>G (p.Arg182Gly)

dbSNP: rs63750211

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075747	SCV000106755	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberration which introduces frameshift (no full-length expressed from allele)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000684818	SCV000255269	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 182 of the MLH1 protein (p.Arg182Gly). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 10480359, 16395668, 19459153, 21404117, 22773173). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90258). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). Studies have shown that this missense change results in skipping of exon 6 and introduces a premature termination codon (PMID: 16395668). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000570187	SCV000669544	pathogenic	Hereditary cancer-predisposing syndrome	2016-08-04	criteria provided, single submitter	clinical testing	The p.R182G pathogenic mutation (also known as c.544A>G), located in coding exon 6 of the MLH1 gene, results from an A to G substitution at nucleotide position 544. The arginine at codon 182 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been identified in multiple families either meeting Amsterdam II criteria or whose family history was suggestive of HNPCC/Lynch syndrome, and has also been shown to co-segregate with disease in a large Irish family (Chong G et al. Hum. Mutat., 2009 Aug;30:E797-812; Hardt K et al. Fam. Cancer, 2011 Jun;10:273-84; Wang Q et al. Int. J. Cancer, 1997 Dec;73:831-6; Farrell MP et al. Fam. Cancer, 2012 Sep;11:509-18). This alteration shows a dominant negative effect in reporter assays in yeast, MMR activity of 74.3% and MLH1 expression of 25-75% compared to wild type (Takahashi M et al. Cancer Res., 2007 May;67:4595-604). This alteration has also been shown to result in skipping and complete loss of coding exon 6 at the mRNA level (Auclair J et al. Hum. Mutat., 2006 Feb;27:145-54). This amino acid position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). This alteration has also been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). Based on the available evidence, this alteration is classified as a pathogenic mutation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353413	SCV000592362	uncertain significance	not provided		no assertion criteria provided	clinical testing