ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.924G>C (p.Glu308Asp) (rs114185660)

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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 RCV000165430 SCV000216159 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000471981 SCV000552034 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 308 of the PMS2 protein (p.Glu308Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs114185660, ExAC 0.01%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 185925). 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. 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 RCV000481332 SCV000565393 uncertain significance not provided 2018-06-08 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.924G>C at the cDNA level, p.Glu308Asp (E308D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. PMS2 Glu308Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). PMS2 Glu308Asp is located in the ATPase domain (Guarne 2001). 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 Glu308Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000165430 SCV000904179 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193854 SCV001363002 uncertain significance not specified 2019-11-20 criteria provided, single submitter clinical testing Variant summary: PMS2 c.924G>C (p.Glu308Asp) results in a conservative amino acid change located in the S5 domain 2-like domain (IPR013507) of 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 2.4e-05 in 251214 control chromosomes (gnomAD). 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.924G>C in individuals affected with Hereditary Non-Polyposis Colon Cancer and no experimental evidence demonstrating its impact on protein function have been reported in the literature. Co-occurrence with another likely pathogenic variant has been observed in our internal database (MSH2 c.2006-2A>T), providing supporting evidence for a benign role. Four ClinVar submitters (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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