ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1363T>C (p.Ser455Pro)

gnomAD frequency: 0.00001  dbSNP: rs1554297839
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000568758 SCV000670752 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-15 criteria provided, single submitter clinical testing The p.S455P variant (also known as c.1363T>C), located in coding exon 11 of the PMS2 gene, results from a T to C substitution at nucleotide position 1363. The serine at codon 455 is replaced by proline, an amino acid with similar properties. This amino acid position is poorly 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.
Invitae RCV001063227 SCV001228064 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-09-27 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 455 of the PMS2 protein (p.Ser455Pro). 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: 484253). 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. 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.
Color Diagnostics, LLC DBA Color Health RCV000568758 SCV001339886 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-29 criteria provided, single submitter clinical testing This missense variant replaces serine with proline at codon 455 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 hereditary cancer in the literature. This variant has been identified in 1/31396 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV003237936 SCV002009117 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing

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