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

gnomAD frequency: 0.00001  dbSNP: rs1554297839

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000568758	SCV000670752	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-18	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.
Labcorp Genetics (formerly Invitae), Labcorp	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