ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1646C>A (p.Ser549Tyr) (rs200447622)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115379 SCV000149288 uncertain significance not specified 2017-04-26 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1646C>A at the cDNA level, p.Ser549Tyr (S549Y) at the protein level, and results in the change of a Serine to a Tyrosine (TCT>TAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ser549Tyr 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 Serine and Tyrosine differ in some properties, this is considered a semi-conservative amino acid substitution and may affect protein integrity. MSH6 Ser549Tyr occurs at a position that is not conserved across species and is located in the MSH2 binding site (Kariola 2002). In silico analyses 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 Ser549Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000546737 SCV000624673 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces serine with tyrosine at codon 549 of the MSH6 protein (p.Ser549Tyr). The serine residue is moderately conserved and there is a large physicochemical difference between serine and tyrosine. This variant is present in population databases (rs200447622, ExAC 0.01%) but has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 127561). 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: "Possibly 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.
Ambry Genetics RCV000575160 SCV000662496 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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