ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.4000C>T (p.Arg1334Trp) (rs773763465)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163638 SCV000214206 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000198598 SCV000254324 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1334 of the MSH6 protein (p.Arg1334Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (ExAC 0.01%). This variant has been reported in an individual with colorectal cancer (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 184389). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000657088 SCV000279624 uncertain significance not provided 2018-04-18 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.4000C>T at the cDNA level, p.Arg1334Trp (R1334W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has been reported in at least one individual with a personal and family history of colon cancer and in one individual with personal history of breast and pancreatic cancer (Chubb 2015, Dudley 2018). MSH6 Arg1334Trp was observed at an allele frequency of 0.013% (3/23,646) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the ATPase domain and the MSH2 binding site (Kariola 2002, Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Arg1334Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000409323 SCV000488106 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000216971 SCV000601597 uncertain significance not specified 2016-12-15 criteria provided, single submitter clinical testing
Color RCV000163638 SCV000685474 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-12 criteria provided, single submitter clinical testing

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