ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1268C>T (p.Ala423Val)

dbSNP: rs756883400
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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 RCV000165790 SCV000216535 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-17 criteria provided, single submitter clinical testing The p.A423V variant (also known as c.1268C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1268. The alanine at codon 423 is replaced by valine, an amino acid with similar properties. This amino acid position is 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.
Color Diagnostics, LLC DBA Color Health RCV000165790 SCV000686117 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-13 criteria provided, single submitter clinical testing
Invitae RCV001217614 SCV001389460 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 423 of the PMS2 protein (p.Ala423Val). 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: 186233). 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.

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