ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3100C>T (p.Arg1034Trp) (rs587779930)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000203004 SCV000257641 uncertain significance Lynch syndrome 2015-03-06 criteria provided, single submitter clinical testing
GeneDx RCV000219542 SCV000279304 uncertain significance not provided 2016-10-20 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3100C>T at the cDNA level, p.Arg1034Trp (R1034W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as a germline variant. However, it has been reported as a somatic variant in a stomach tumor sample according to the Catalogue of Somatic Mutations in Cancer (COSMIC) database. MSH6 Arg1034Trp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg1034Trp occurs at a position that is conserved across species and is located within domain III of the MutS domain (Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH6 Arg1034Trp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000410374 SCV000488920 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-07-18 criteria provided, single submitter clinical testing
Invitae RCV000524152 SCV000551047 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1034 of the MSH6 protein (p.Arg1034Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs587779930, ExAC 0.003%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 218431). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000203004 SCV000837908 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000774606 SCV000908408 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000774606 SCV001179911 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-19 criteria provided, single submitter clinical testing Insufficient or conflicting evidence

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