ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1481C>T (p.Ser494Leu) (rs587782602)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131960 SCV000187017 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-08 criteria provided, single submitter clinical testing Insufficient or Conflicting Evidence
Invitae RCV000168413 SCV000219107 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 494 of the PMS2 protein (p.Ser494Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs587782602, ExAC 0.001%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 142635). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000223568 SCV000279992 uncertain significance not provided 2018-11-15 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1481C>T at the cDNA level, p.Ser494Leu (S494L) 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 a pathogenic or benign germline variant. Although this variant was observed in large population cohorts, data in this region of PMS2 are not considered reliable due to high pseudogene homology (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 Ser494Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000662631 SCV000785307 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-07-07 criteria provided, single submitter clinical testing
Color RCV000131960 SCV000903112 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193253 SCV001361981 uncertain significance not specified 2019-10-21 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1481C>T (p.Ser494Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251430 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1481C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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