Submissions for variant NM_000535.7(PMS2):c.773G>A (p.Ser258Asn)

dbSNP: rs587780727

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123091	SCV000166391	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-04-07	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 135945). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 258 of the PMS2 protein (p.Ser258Asn).
GeneDx	RCV000478367	SCV000570937	uncertain significance	not provided	2016-07-11	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.773G>A at the cDNA level, p.Ser258Asn (S258N) at the protein level, and results in the change of a Serine to an Asparagine (AGC>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Ser258Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. PMS2 Ser258Asn occurs at a position that is not conserved and is located in the ATPase domain (Fukui 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 Ser258Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000771589	SCV000904185	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-04	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 258 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 not been identified 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.
Ambry Genetics	RCV000771589	SCV001189214	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-24	criteria provided, single submitter	clinical testing	The p.S258N variant (also known as c.773G>A), located in coding exon 7 of the PMS2 gene, results from a G to A substitution at nucleotide position 773. The serine at codon 258 is replaced by asparagine, an amino acid with highly 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.