ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.793C>A (p.Arg265Ser) (rs63751194)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075871 SCV000106885 pathogenic Lynch syndrome 2018-10-18 reviewed by expert panel curation Paper by Van der Klift et al. 2015 shows aberrant splicing (exon 10 exclusion) in patient sample and minigene assay, confirmed by minigene assay in Soukarieh et al., 2016 (Plos Genet).
Ambry Genetics RCV000567864 SCV000664835 pathogenic Hereditary cancer-predisposing syndrome 2017-01-30 criteria provided, single submitter clinical testing The p.R265S pathogenic mutation (also known as c.793C>A), located in coding exon 10 of the MLH1 gene, results from a C to A substitution at nucleotide position 793. The arginine at codon 265 is replaced by serine, an amino acid with dissimilar properties. This alteration has been classified as likely 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 []). This alteration is located in the ATP-binding domain of the MLH1 protein and has been demonstrated to reduce mismatch repair proficiency in two different yeast strains when compared to wildtype (Wanat JJ et al. Hum. Mol. Genet. 2007 Feb;16:445-52). An in vitro functional assay by Drost et al. also demonstrated that the p.R265S alteration leads to a decrease in mismatch repair proficiency—to below 25% when compared to wildtype (Drost M et al. Hum. Mutat. 2010 Mar;31:247-53). Additionally, minigene and RNA assays have shown that this alteration results in a transcript with near-complete skipping of exon 10 (van der Klift HM et al. Mol Genet Genomic Med. 2015 Jul;3:327-45; Soukarieh O et al. PLoS Genet. 2016 Jan;12:e1005756). This alteration has been identified in multiple individuals with Lynch/HNPCC-related cancers, of which many had tumors with high microsatellite instability and either loss of isolated MLH1 protein or loss of both MLH1 and PMS2 proteins on immunohistochemistry (Zavodna K et al. Neoplasma. 2006;53:269-76; Alemayehu A et al. Genes Chromosomes Cancer. 2008 Oct;47:906-14; Hardt K et al. Fam. Cancer. 2011 Jun;10:273-84; Ferguson SE et al. Cancer. 2014 Dec;120:3932-9). Based on the available evidence, p.R265S is classified as a pathogenic mutation.
University of Washington Department of Laboratory Medicine, University of Washington RCV000075871 SCV000887314 likely pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MLH1 NM_000249.3:c.793C>A has a 97.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.
Invitae RCV001070683 SCV001235949 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-04-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 265 of the MLH1 protein (p.Arg265Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Lynch-related cancer in a family (PMID: 16830052) and reported in several individuals affected with colorectal cancer or Lynch syndrome (PMID: 25081409, 27435373, 16636019, 21404117). ClinVar contains an entry for this variant (Variation ID: 90380). This variant has been reported to affect MLH1 protein function (PMID: 20020535, 17210669). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 26247049). Based on a multifactorial likelihood algorithm using genetic data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). This variant disrupts the p.Arg265 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12386821, 15713769, 19419416, 20587412, 20864636, 12386821, 15713769, 18561205). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000202126 SCV000257116 pathogenic not provided no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353449 SCV000592379 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The p.Arg265Ser variant has been previously reported in the literature (Zavodna_2006_16830052, Alemayehu_2008_18618713, Niessen_2006_16636019). It was identified in 3 out of 572 proband chromosomes (frequency 0.005) in individuals with colorectal cancer, however, no normal population controls were included in these studies. In addition, this variant has been previously reported by our laboratory in two families. In one family the variant was shown to segregate with disease in 4 affected individuals with Lynch syndrome (two were obligate carriers), and did not segregate in at least two unaffected individuals, increasing the likelihood this variant is pathogenic. The p.Arg265 residue is conserved across mammals/species and computational analyses (PolyPhen, SIFT, AlignGVGD, BLOSUM, MAPP-MMR) suggest that the p.Arg265Ser variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. However, functional studies including in vitro MMR complementation assays, protein expression assays, promoter methylation studies, LOH analysis, and a yeast-based reversion rate assay, suggests this variant is likely pathogenic (Drost_2010_20020535, Alemayehu_2008_18618713, Wanat_2007_17210669). Of note, another variant at the same nucleotide position (c.793C>T) causing a different missense substitution (p.Arg265Cys) has been previously identified in Lynch Syndrome families in literature and by our laboratory, has been well-characterized by similar functional studies as the p.Arg265Ser variant, and has been classified as pathogenic, further suggesting that p.Arg265Ser may also have clinical significance. In summary, based on the above information this variant meets our laboratory's criteria to be classified as Pathogenic.
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249943 SCV001423885 pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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