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).
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075871 SCV000592379 pathogenic Lynch syndrome 2013-04-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV000567864 SCV000664835 pathogenic Hereditary cancer-predisposing syndrome 2017-01-30 criteria provided, single submitter clinical testing Other strong data supporting pathogenic classification;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s)
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 colon cancer 2019-04-13 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 Genetic Testing Laboratories,Mayo Clinic RCV000202126 SCV000257116 pathogenic not provided no assertion criteria provided research
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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