ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1403G>C (p.Arg468Pro) (rs41295268)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223504 SCV000277645 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000456959 SCV000551225 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 468 of the MSH6 protein (p.Arg468Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 233298). 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 and their clinical significance is uncertain. 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.
GeneDx RCV000486815 SCV000571091 uncertain significance not provided 2018-03-06 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1403G>C at the cDNA level, p.Arg468Pro (R468P) at the protein level, and results in the change of an Arginine to a Proline (CGT>CCT). This variant has been observed in at least one individual with endometrial cancer (Ring 2016). MSH6 Arg468Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the mismatch binding domain (Warren 2007, Kansikas 2011). Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In addition, multiple splicing models predict that this variant may create or enhance a cryptic splice acceptor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether MSH6 Arg468Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000223504 SCV000690198 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486815 SCV001134394 uncertain significance not provided 2019-03-12 criteria provided, single submitter clinical testing

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