ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1765G>C (p.Asp589His) (rs749727182)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483031 SCV000566221 uncertain significance not provided 2018-12-27 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1765G>C at the cDNA level, p.Asp589His (D589H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAC>CAC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. Although this variant was observed in large population cohorts, 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 Asp589His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000548259 SCV000625557 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-10 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 589 of the PMS2 protein (p.Asp589His). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 418854). 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, this variant has uncertain impact on PMS2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000561065 SCV000663463 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-09 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000561065 SCV000911777 likely benign Hereditary cancer-predisposing syndrome 2016-03-03 criteria provided, single submitter clinical testing

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