ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1499C>G (p.Ser500Cys)

gnomAD frequency: 0.00002  dbSNP: rs375905814
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478044 SCV000567104 uncertain significance not provided 2023-10-23 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV000525015 SCV000625529 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-11-19 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 500 of the PMS2 protein (p.Ser500Cys). This variant is present in population databases (rs375905814, gnomAD 0.007%). 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: 419358). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. 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 RCV000563556 SCV000663529 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-09 criteria provided, single submitter clinical testing The p.S500C variant (also known as c.1499C>G), located in coding exon 11 of the PMS2 gene, results from a C to G substitution at nucleotide position 1499. The serine at codon 500 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is not 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 RCV000563556 SCV004359602 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-17 criteria provided, single submitter clinical testing This missense variant replaces serine with cysteine at codon 500 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 1/251412 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.
Baylor Genetics RCV004568162 SCV005056447 uncertain significance Lynch syndrome 4 2024-01-25 criteria provided, single submitter clinical testing

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