ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1582G>A (p.Gly528Ser)

gnomAD frequency: 0.00001  dbSNP: rs1354150928
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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 RCV001180908 SCV001345960 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-20 criteria provided, single submitter clinical testing This missense variant replaces glycine with serine at codon 528 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 been identified in 2/251018 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 RCV001876004 SCV002311699 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-11-15 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 528 of the PMS2 protein (p.Gly528Ser). This variant is present in population databases (no rsID available, 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: 921468). 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.
Ambry Genetics RCV001180908 SCV004061424 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-24 criteria provided, single submitter clinical testing The p.G528S variant (also known as c.1582G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1582. The glycine at codon 528 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. 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.
All of Us Research Program, National Institutes of Health RCV004006698 SCV004844176 uncertain significance Lynch syndrome 2023-08-15 criteria provided, single submitter clinical testing

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