ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1384A>G (p.Ile462Val)

gnomAD frequency: 0.00001  dbSNP: rs200116037
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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 RCV000571937 SCV000674238 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-09 criteria provided, single submitter clinical testing The p.I462V variant (also known as c.1384A>G), located in coding exon 11 of the PMS2 gene, results from an A to G substitution at nucleotide position 1384. The isoleucine at codon 462 is replaced by valine, an amino acid with highly similar properties. This variant was reported in 1/60,466 breast cancer cases and in 4/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is poorly 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 RCV000686148 SCV000813652 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-11-10 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 462 of the PMS2 protein (p.Ile462Val). This variant is present in population databases (rs200116037, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 35449176). ClinVar contains an entry for this variant (Variation ID: 486044). 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 with a negative predictive value of 80%. 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.
Color Diagnostics, LLC DBA Color Health RCV000571937 SCV000908256 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-10 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 462 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. In a large breast cancer case-control study, this variant has been reported in 1/60466 cases and 4/53461 unaffected controls (PMID: 33471991). This variant has been identified in 2/251492 chromosomes 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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