Submissions for variant NM_000535.7(PMS2):c.100A>C (p.Ser34Arg)

dbSNP: rs730881912

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160889	SCV000211581	uncertain significance	not provided	2015-05-29	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.100A>C at the cDNA level, p.Ser34Arg (S34R) at the protein level, and results in the change of a Serine to an Arginine (AGT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Ser34Arg was not observed in approximately 3,700 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Serine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Ser34Arg occurs at a position that is conserved in mammals and is located in the ATPase domain (Fukui 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether PMS2 Ser34Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000216392	SCV000274297	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-10	criteria provided, single submitter	clinical testing	The p.S34R variant (also known as c.100A>C), located in coding exon 2 of the PMS2 gene, results from an A to C substitution at nucleotide position 100. The serine at codon 34 is replaced by arginine, 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 inconclusive by in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000548098	SCV000625493	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-06-09	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 34 of the PMS2 protein (p.Ser34Arg). 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: 182804). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160889	SCV001470598	uncertain significance	not provided	2019-12-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998525	SCV004826596	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 34 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders 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.