Submissions for variant NM_000535.7(PMS2):c.1511A>G (p.Glu504Gly)

dbSNP: rs1254121331

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000556082	SCV000625533	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 504 of the PMS2 protein (p.Glu504Gly). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 35451682). ClinVar contains an entry for this variant (Variation ID: 455656). 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	RCV000569319	SCV000663450	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-19	criteria provided, single submitter	clinical testing	The p.E504G variant (also known as c.1511A>G), located in coding exon 11 of the PMS2 gene, results from an A to G substitution at nucleotide position 1511. The glutamic acid at codon 504 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well 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.
Mendelics	RCV000708982	SCV000838177	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000569319	SCV000906809	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-25	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 504 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 1/251394 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800736	SCV002046262	uncertain significance	not specified	2020-10-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000708982	SCV004844195	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 504 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 1/251394 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.