ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.695G>A (p.Gly232Glu) (rs201811667)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000034633 SCV000279321 uncertain significance not provided 2018-01-02 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.695G>A at the cDNA level, p.Gly232Glu (G232E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGG>GAG). This variant was observed in 1/572 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). PMS2 Gly232Glu was not observed in large population cohorts (Lek 2016). PMS2 Gly232Glu is located within the ATPase domain (Guarne 2001). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Gly232Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000569102 SCV000663473 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Counsyl RCV000662682 SCV000785392 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-08-02 criteria provided, single submitter clinical testing
Invitae RCV000800172 SCV000939872 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 232 of the PMS2 protein (p.Gly232Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 41717). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Integrated Genetics/Laboratory Corporation of America RCV001193966 SCV001363162 uncertain significance not specified 2019-05-06 criteria provided, single submitter clinical testing Variant summary: PMS2 c.695G>A (p.Gly232Glu) results in a non-conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.695G>A has been reported in the literature in an individual affected with atherosclerosis (Johnston_2012). This report however, does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034633 SCV000043435 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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