ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2176C>T (p.Pro726Ser)

dbSNP: rs1407555810
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000572946 SCV000670787 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-18 criteria provided, single submitter clinical testing The p.P726S variant (also known as c.2176C>T), located in coding exon 13 of the PMS2 gene, results from a C to T substitution at nucleotide position 2176. The proline at codon 726 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV002526884 SCV002965072 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2022-05-24 criteria provided, single submitter clinical testing The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 484274). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 726 of the PMS2 protein (p.Pro726Ser). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.

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