ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2386G>A (p.Val796Ile) (rs368737800)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212872 SCV000149594 uncertain significance not provided 2018-05-02 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2386G>A at the cDNA level, p.Val796Ile (V796I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). PMS2 Val796Ile has been identified in at least one individual with colon cancer, as well as in individuals undergoing multigene cancer panel testing due to a history of breast cancer or a Lynch syndrome-related cancer and/or polyps (Yurgelun 2015, Pearlman 2016, Tung 2016). 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 Val796Ile is located in the endouclease domain (Fukui 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether PMS2 Val796Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115685 SCV000186210 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-09 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000465421 SCV000551956 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-01-07 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 796 of the PMS2 protein (p.Val796Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. The frequency data for this variant in the population databases (rs368737800, ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed in individuals affected with breast cancer (PMID: 26976419), clinical features of Lynch syndrome (PMID: 25980754), and colon cancer (PMID: 27978560). However, for the latter observation, it was not clearly determined whether the variant occurred in PMS2 or a PMS2-pseudogene in that individual (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 127781). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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