ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2314C>T (p.Arg772Trp) (rs63750138)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162422 SCV000212763 likely pathogenic Hereditary cancer-predisposing syndrome 2017-09-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification
Color RCV000162422 SCV000908396 likely pathogenic Hereditary cancer-predisposing syndrome 2018-05-10 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074732 SCV000592604 likely pathogenic Lynch syndrome 2013-06-05 criteria provided, single submitter clinical testing
GeneDx RCV000218399 SCV000279102 likely pathogenic not provided 2018-05-02 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2314C>T at the cDNA level, p.Arg772Trp (R772W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant was observed in multiple individuals with a personal and/or family history of Lynch-syndrome associated cancers (Plaschke 2004, Jasperson 2008, Buchanan 2014). In these studies, immunohistochemistry performed on three colon tumors and one endometrial tumor showed either reduction or loss of MSH6 expression. MSH6 Arg772Trp was also observed in the homozygous state in three children reported to have constitutional mismatch repair deficiency (CMMR-D) syndrome and immunohistochemistry performed on skin biopsies procured from two of these children were found to be deficient in MSH6 expression (Elhasid 2015, Levi 2015). MSH6 Arg772Trp was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg772Trp occurs at a position that is conserved across species and is located within the lever domain (Warren 2007, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider MSH6 Arg772Trp to be a likely pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000074732 SCV000695806 pathogenic Lynch syndrome 2019-02-15 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2314C>T (p.Arg772Trp) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function (ACMG PP3). The variant allele was found at a frequency of 8.1e-06 in 246050 control chromosomes (gnomAD and publication, ACMG PM2). c.2314C>T has been reported in the literature in individuals affected with Lynch Syndrome, colon cancer, endometrial cancer and breast cancer (Plaschke 2004, Buchanan 2014, Sunga 2017, Lu_2018). The reported patients ranged from those fulfilling the Amsterdam-II criteria (Jasperson 2008), revised Bethesda guidelines (Buchanan 2014) as well as not fulfilling the Bethesda guidelines (Plaschke 2004). In addition, in one comprehensively genotyped patient affected by colon and urinary bladder cancer who had reduced expression of the MSH6 protein within the tumor (and normal expression of MLH1 and MSH2) the variant was also found in her affected mother (Jasperson 2008). Loss of MSH6 expression in tumors was also noted in other studies for individuals carrying the variant (Plaschke 2004, Buchanan 2014). Furthermore, this variant has been reported in homozygous state associated with the phenotype for constitutional mismatch repair deficiency (CMMR-D) syndrome; immunohistochemical analysis of skin biopsies revealed MSH6 protein deficiency (Elhasid 2015, Levi 2015). The variant was also found in one female endometrial cancer patient (47 y.o.) as a somatic variant, who carried a frameshift 19bps insertion in MSH6 as a germ-line variant (Goodfellow 2003). Lastly, somatic point mutations affecting a different nucleotide but the same amino acid residue (c.2315G>A [p.R772Q]), have been identified in a colon and a gastric cancer, both with the MSI-H phenotype (Ohmiya et al., 2001). This points to p.Arg772Trp fulfilling the LOH (Loss of Heterozygosity) criteria for tumor suppressor genes and highlighting functional importance of this residue within the MSH6 protein. These data indicate that the variant is likely to be associated with disease (ACMG PS4). A co-occurrence with another pathogenic variant has been reported in our internal database (CHEK2 c.1434delA, p.Glu479fsX3). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) has recently classified this variant as a class-5 pathogenic variant using the same evidence outlined above. Based on the evidence outlined above, the variant meets sufficient clinical criteria to be classified as pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074732 SCV000107941 pathogenic Lynch syndrome 2018-10-18 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV000524139 SCV000551232 likely pathogenic Hereditary nonpolyposis colon cancer 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 772 of the MSH6 protein (p.Arg772Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Lynch syndrome, constitutional mismatch repair deficiency, colorectal cancer, and endometrial cancer (PMID: 18176851, 25307252, 14974087, 24323032, 28449805). This variant has also been reported in individuals with suspected Lynch syndrome (PMID: 28514183). ClinVar contains an entry for this variant (Variation ID: 89267). Algorithms developed specifically for the MSH6 gene suggest that this missense change is likely to be deleterious (PMID: 23621914, 26333163). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000218399 SCV000691930 pathogenic not provided no assertion criteria provided clinical testing

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