ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1508C>A (p.Ser503Tyr)

gnomAD frequency: 0.00001  dbSNP: rs777920014
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000581195 SCV000691025 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-27 criteria provided, single submitter clinical testing This missense variant replaces serine with tyrosine at codon 503 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 been reported in an individual with stomach adenocarcinoma (PMID: 26689913). This variant has been identified in 3/282758 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.
Invitae RCV000704266 SCV000833208 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-11-27 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 503 of the PMS2 protein (p.Ser503Tyr). This variant is present in population databases (rs777920014, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 35449176). ClinVar contains an entry for this variant (Variation ID: 492257). 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 with a positive 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.
Ambry Genetics RCV000581195 SCV001172333 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-12 criteria provided, single submitter clinical testing The p.S503Y variant (also known as c.1508C>A), located in coding exon 11 of the PMS2 gene, results from a C to A substitution at nucleotide position 1508. The serine at codon 503 is replaced by tyrosine, an amino acid with dissimilar 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.
GeneDx RCV001755977 SCV002007295 uncertain significance not provided 2019-12-26 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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