ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.364A>C (p.Ile122Leu) (rs761748894)

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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 RCV000164722 SCV000215393 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-18 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000473137 SCV000552043 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 122 of the PMS2 protein (p.Ile122Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 185323). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000478101 SCV000567917 uncertain significance not provided 2018-06-14 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.364A>C at the cDNA level, p.Ile122Leu (I122L) at the protein level, and results in the change of an Isoleucine to a Leucine (ATT>CTT). This variant was observed in at least one individual with a personal history of colon cancer (Yehia 2018). PMS2 Ile122Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Guarne 2001). 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 Ile122Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000164722 SCV000691072 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-13 criteria provided, single submitter clinical testing
Counsyl RCV000663011 SCV000786026 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-02-06 criteria provided, single submitter clinical testing

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