ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.98G>C (p.Arg33Pro) (rs878853751)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000230339 SCV000283866 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 33 of the MSH6 protein (p.Arg33Pro). The arginine residue is weakly 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 reported in an individual with colorectal cancer (PMID: 23523604). ClinVar contains an entry for this variant (Variation ID: 237219). 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 tolerated, but these predictions have not been confirmed by published functional studies. 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 RCV000487300 SCV000568718 uncertain significance not provided 2016-05-02 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.98G>C at the cDNA level, p.Arg33Pro (R33P) at the protein level, and results in the change of an Arginine to a Proline (CGT>CCT). This variant was observed in at least one individual with early-onset colorectal cancer whose tumor was microsatellite stable (Pérez-Cabornero 2013). MSH6 Arg33Pro was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg33Pro occurs at a position that is not conserved and is not located in a known functional domain (Terui 2013). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Arg33Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000575454 SCV000664865 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-01 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000575454 SCV000911681 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-21 criteria provided, single submitter clinical testing

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