ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1204C>G (p.Gln402Glu) (rs587782789)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478508 SCV000569912 uncertain significance not provided 2016-04-09 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1204C>G at the cDNA level, p.Gln402Glu (Q402E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Gln402Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamine and Glutamic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Gln402Glu occurs at a position that is not conserved and is not located in a known functional domain (Fukui 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 Gln402Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000562801 SCV000674242 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-31 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000630066 SCV000751022 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-03-15 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 402 of the PMS2 protein (p.Gln402Glu). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine 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: 420890). 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.

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