ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1586C>T (p.Ser529Leu) (rs876658794)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217760 SCV000274495 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-11 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000471239 SCV000551968 uncertain significance Hereditary nonpolyposis colon cancer 2019-09-02 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 529 of the PMS2 protein (p.Ser529Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 230822). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect 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 RCV000486303 SCV000565415 uncertain significance not provided 2017-10-19 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1586C>T at the cDNA level, p.Ser529Leu (S529L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Ser529Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Ser529Leu occurs at a position that is not conserved and is not located in a known functional domain. 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 PMS2 Ser529Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000217760 SCV000903483 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-18 criteria provided, single submitter clinical testing

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