Submissions for variant NM_000249.4(MLH1):c.104T>G (p.Met35Arg)

dbSNP: rs63749906

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075100	SCV000106092	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269567	SCV001449644	pathogenic	not provided	2016-04-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399429	SCV002706079	pathogenic	Hereditary cancer-predisposing syndrome	2017-11-13	criteria provided, single submitter	clinical testing	The p.M35R pathogenic mutation (also known as c.104T>G), located in coding exon 1 of the MLH1 gene, results from a T to G substitution at nucleotide position 104. The methionine at codon 35 is replaced by arginine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. This mutation, designated Met35>Arg (ATG>AGG), segregated with disease in a Swedish family meeting Amsterdam criteria (Tannergård P et al. Cancer Res. 1995 Dec;55:6092-6) and was identified in an individual with HNPCC whose two adenomas with low grade dysplasia demonstrated absent MLH1 and PMS2 by immunohistochemistry (Halvarsson B et al. Mod. Pathol. 2005 Aug;18:1095-101). In yeast functional assays, the M35R variant showed a mutator phenotype when compared to wild type suggesting inactivation of mismatch repair (Shcherbakova PV et al. Mol. Cell. Biol. 1999 Apr;19:3177-83). In a yeast two-hybrid assay, M35R displayed almost no beta-galactosidase activity similar to known deleterious alterations (Kondo E et al. Cancer Res. 2003 Jun;63:3302-8). Additionally, the M35R variant demonstrated no dominant mutator effect in reporter assays in yeast, which is consistent with pathogenicity (Shimodaira H et al. Nat Genet. 1998 Aug;19(4):384-9; 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/]). 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 EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003451002	SCV004187257	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-10	criteria provided, single submitter	clinical testing	This variant is considered likely 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: 8521398]. This variant is expected to disrupt protein structure [Myriad internal data].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353714	SCV000592331	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Met35Arg variant has not been previously identified in our laboratory, but has been reported in the literature in at least 4/245 probands (0.008 frequency) with HNPCC and was absent from 146 controls (Tannergard 1995, Halvarsson 2005, Poley 2007, Lagerstedt Robinson 2007). Of these studies, the variant was found in individuals who either had MLH1 deficient immunohistochemistry or MSI positive tumors (Halvarsson 2005, Poley 2007, Lagerstedt Robinson 2007), increasing the likelihood this variant is pathogenic. In one family, the variant segregated with disease (Tannergard 1995). The p.Met35 residue is conserved across mammals and other vertebrate species, and computational analyses (SIFT, AlignGVGD) predict a deleterious impact on protein function. Although this information is not predictive enough to assume pathogenicity, functional studies have shown that the p.Met35Arg variant showed a reduction in repair capacity compared to the wild-type protein (Lastella 2006, Takahashi_2007_17510385, Shcherbakova_1999_10082584, Kondo_2003_12810663), increasing the likelihood that an alteration to this residue is pathogenic. In addition, this variant has not been observed in more than 1200 proband chromosomes sequenced for the MLH1 gene by our laboratory, increasing the likelihood, this is a rare variant of clinical significance. In summary, based on the above information, this variant is classified as pathogenic.