ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.667A>G (p.Ile223Val)

gnomAD frequency: 0.00001  dbSNP: rs876660067
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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 RCV000221248 SCV000277178 uncertain significance Hereditary cancer-predisposing syndrome 2021-10-13 criteria provided, single submitter clinical testing The p.I223V variant (also known as c.667A>G), located in coding exon 6 of the PMS2 gene, results from an A to G substitution at nucleotide position 667. The isoleucine at codon 223 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000629682 SCV000750638 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-10-05 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 223 of the PMS2 protein (p.Ile223Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 232911). 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 not expected to disrupt PMS2 protein function. 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002267963 SCV002550749 uncertain significance not specified 2024-02-06 criteria provided, single submitter clinical testing
Baylor Genetics RCV003462506 SCV004205384 uncertain significance Lynch syndrome 4 2023-10-16 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003998010 SCV004834206 uncertain significance Lynch syndrome 2023-08-15 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 223 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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