ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1399G>A (p.Val467Ile) (rs373611083)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131574 SCV000186580 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-02 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000457616 SCV000551955 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 467 of the PMS2 protein (p.Val467Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs373611083, ExAC 0.03%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 142447). 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, 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.
GeneDx RCV000656947 SCV000565403 uncertain significance not provided 2018-07-20 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1399G>A at the cDNA level, p.Val467Ile (V467I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). 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 Val467Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485817 SCV000601817 uncertain significance not specified 2017-03-24 criteria provided, single submitter clinical testing
Color RCV000131574 SCV000903129 likely benign Hereditary cancer-predisposing syndrome 2015-11-25 criteria provided, single submitter clinical testing
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249988 SCV001424002 uncertain significance Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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