ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3350G>T (p.Cys1117Phe) (rs773245315)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000230242 SCV000283800 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-08-19 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 1117 of the MSH6 protein (p.Cys1117Phe). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is present in population databases (rs773245315, ExAC 0.009%) but has not been reported in the literature in individuals with an MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 237188). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000487138 SCV000568034 uncertain significance not provided 2015-09-21 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3350G>T at the cDNA level, p.Cys1117Phe (C1117F) at the protein level, and results in the change of a Cysteine to a Phenylalanine (TGT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Cys1117Phe 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 Cysteine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Cys1117Phe occurs at a position that is conserved in mammals and is not located in a known functional domain (Kariola 2002, Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Cys1117Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000570386 SCV000662389 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-20 criteria provided, single submitter clinical testing Insufficient or conflicting evidence

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