ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1267G>T (p.Ala423Ser)

gnomAD frequency: 0.00001  dbSNP: rs587778619
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000706603 SCV000835665 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-08-27 criteria provided, single submitter clinical testing 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 not expected to disrupt PMS2 protein function. ClinVar contains an entry for this variant (Variation ID: 582511). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 423 of the PMS2 protein (p.Ala423Ser). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions.
Ambry Genetics RCV001010662 SCV001170894 uncertain significance Hereditary cancer-predisposing syndrome 2022-08-25 criteria provided, single submitter clinical testing The p.A423S variant (also known as c.1267G>T), located in coding exon 11 of the PMS2 gene, results from a G to T substitution at nucleotide position 1267. The alanine at codon 423 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other 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.

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