ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1510G>C (p.Glu504Gln) (rs368516768)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162805 SCV000213286 likely benign Hereditary cancer-predisposing syndrome 2018-06-13 criteria provided, single submitter clinical testing Conflicting evidence
Invitae RCV000524435 SCV000551992 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 504 of the PMS2 protein (p.Glu504Gln). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs368516768, ExAC 0.005%). This variant has been reported in an individual with suspected Lynch syndrome and in an individual with colorectal cancer (PMID: 27435373, 28135145). ClinVar contains an entry for this variant (Variation ID: 91305). An experimental study has shown that this missense change does not affect PMS2 mismatch-repair activity in vitro (PMID: 27435373). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000483703 SCV000565408 uncertain significance not provided 2018-12-10 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1510G>C at the cDNA level, p.Glu504Gln (E504Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAG>CAG). This variant has been observed in at least two individuals with colorectal cancer, one tumor was identified to have microsatellite instability (MSI-H) and loss of MLH1 and PMS2 proteins on mismatch repair immunohistochemistry (van der Klift 2016, Yurgelun 2017). However, van der Klift et al. (2016) also demonstrated that this variant was proficient in mismatch repair (MMR) activity in an in vitro MMR assay. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as uncertain based on insufficient evidence (Thompson 2014). Although this variant was observed in large population cohorts, population 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 Glu504Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000162805 SCV000686132 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780617 SCV000918036 uncertain significance not specified 2019-09-06 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1510G>C (p.Glu504Gln) results in a 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. Several computational tools predict a significant impact on normal splicing: Two predict the variant creates an alternative 3 prime acceptor site. One predicts the variant strengthens this alternative 3 prime acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.8e-05 in 251388 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1510G>C, has been reported in the literature in individuals affected with suspected Lynch Syndrome or colorectal cancer (van der Klift_2016, Yurgelum_2017). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At least one publication, van der Klift_2016, reports this variant was proficient in mismatch repair (MMR) activity, showing no damaging effect of this variant. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (3x VUS, 1x likely benign). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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