Submissions for variant NM_000535.7(PMS2):c.58C>G (p.Arg20Gly)

dbSNP: rs573374779

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000468998	SCV000552068	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 20 of the PMS2 protein (p.Arg20Gly). This variant is present in population databases (rs573374779, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 411083). 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 with a negative predictive value of 80%. 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.
Ambry Genetics	RCV000561984	SCV000663457	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-07	criteria provided, single submitter	clinical testing	The p.R20G variant (also known as c.58C>G), located in coding exon 2 of the PMS2 gene, results from a C to G substitution at nucleotide position 58. The arginine at codon 20 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer diagnosed over age 50 who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). 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.
Color Diagnostics, LLC DBA Color Health	RCV000561984	SCV001341288	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 20 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26976419). This variant has been identified in 2/245594 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.
GeneDx	RCV002289614	SCV002578785	uncertain significance	not provided	2022-11-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11574484, 26976419)