ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1757C>G (p.Ser586Cys)

dbSNP: rs1335723102
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001226703 SCV001399025 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-08 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 586 of the PMS2 protein (p.Ser586Cys). 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: 954268). 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 RCV003346393 SCV004052672 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-29 criteria provided, single submitter clinical testing The p.S586C variant (also known as c.1757C>G), located in coding exon 11 of the PMS2 gene, results from a C to G substitution at nucleotide position 1757. The serine at codon 586 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.

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