ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2391G>A (p.Met797Ile)

dbSNP: rs1554293841
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563840 SCV000663446 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-24 criteria provided, single submitter clinical testing The p.M797I variant (also known as c.2391G>A), located in coding exon 14 of the PMS2 gene, results from a G to A substitution at nucleotide position 2391. The methionine at codon 797 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000630212 SCV000751168 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-06-09 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with PMS2-related conditions. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function. ClinVar contains an entry for this variant (Variation ID: 480303). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 797 of the PMS2 protein (p.Met797Ile).
GeneDx RCV001775884 SCV002012653 uncertain significance not provided 2019-10-29 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge

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