ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2332T>A (p.Phe778Ile) (rs876660374)

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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 RCV000216483 SCV000277755 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-21 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000766549 SCV000567653 uncertain significance not provided 2018-08-02 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2332T>A at the cDNA level, p.Phe778Ile (F778I) at the protein level, and results in the change of a Phenylalanine to an Isoleucine (TTC>ATC). 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 GENE are not considered reliable due to high pseudogene homology (Lek 2016). PMS2 Phe778Ile 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 information, it is unclear whether PMS2 Phe778Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486115 SCV000601842 uncertain significance not specified 2017-07-19 criteria provided, single submitter clinical testing
GeneKor MSA RCV000216483 SCV000822131 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000697244 SCV000825842 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with isoleucine at codon 778of the PMS2 protein (p.Phe778Ile). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and isoleucine. 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: 233391). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; 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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