ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2035A>G (p.Ile679Val) (rs587780047)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212866 SCV000149580 uncertain significance not provided 2018-07-05 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2035A>G at the cDNA level, p.Ile679Val (I679V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. 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). PMS2 Ile679Val 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 Ile679Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115671 SCV000216046 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-19 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign)
Invitae RCV000547118 SCV000625580 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 679 of the PMS2 protein (p.Ile679Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. The frequency data for this variant in the population databases (rs587780047, ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 127771). 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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