ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2002T>C (p.Ser668Pro) (rs876661080)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000219193 SCV000279470 uncertain significance not provided 2016-11-08 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2002T>C at the cDNA level, p.Ser668Pro (S668P) at the protein level, and results in the change of a Serine to a Proline (TCC>CCC). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. MSH6 Ser668Pro was not observed in approximately 6,500 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 Serine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ser668Pro occurs at a position that is not conserved and is located in MutS domain II (Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Ser668Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000562974 SCV000662551 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-17 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV001054199 SCV001218502 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-03-29 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 668 of the MSH6 protein (p.Ser668Pro). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 234550). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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