ClinVar Miner

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

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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 RCV000162805 SCV000213286 likely benign Hereditary cancer-predisposing syndrome 2017-04-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
Color RCV000162805 SCV000686132 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-13 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America RCV000780617 SCV000918036 uncertain significance not specified 2017-09-18 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1510G>C (p.Glu504Gln) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 10/277148 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0071% (9/126660). However, the technology utalized for this dataset do not rule out pseudogene interference and thus this data cannot be relied upon. The variant of interest has been reported in affected individuals, however without convincing evidence for a pathogenic role (van der Klift 2016, Yurgelun 2017). In addition, in a functional study the variant PMS2 protein was shown to be MMR proficient (van der Klift 2016). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a VUS - possibly benign, until additional information becomes available.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076813 SCV000108299 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000524435 SCV000551992 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-31 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.

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