ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2338C>A (p.Pro780Thr) (rs1064796041)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480063 SCV000572423 uncertain significance not provided 2019-01-03 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2338C>A at the cDNA level, p.Pro780Thr (P780T) at the protein level, and results in the change of a Proline to a Threonine (CCC>ACC). 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). Since Proline and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Pro780Thr is located in the endonuclease domain (Fukui 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Pro780Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000573429 SCV000670833 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-10 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000630117 SCV000751073 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-03-19 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 780 of the PMS2 protein (p.Pro780Thr). The proline residue is moderately conserved and there is a small physicochemical difference between proline and threonine. The frequency data for this variant in the population databases (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: 422851). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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