ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1430C>A (p.Ser477Tyr) (rs876661291)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000217395 SCV000280002 uncertain significance not provided 2018-08-29 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1430C>A at the cDNA level, p.Ser477Tyr (S477Y) at the protein level, and results in the change of a Serine to a Tyrosine (TCC>TAC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. PMS2 Ser477Tyr was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Ser477Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000472890 SCV000551940 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-18 criteria provided, single submitter clinical testing This sequence change replaces serine with tyrosine at codon 477 of the PMS2 protein (p.Ser477Tyr). The serine residue is weakly conserved and there is a large physicochemical difference between serine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 234914). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on PMS2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000563463 SCV000670817 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-13 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000563463 SCV000686126 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-24 criteria provided, single submitter clinical testing

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