Submissions for variant NM_000535.7(PMS2):c.1924G>A (p.Glu642Lys)

dbSNP: rs752772040

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001013714	SCV001174335	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-01	criteria provided, single submitter	clinical testing	The p.E642K variant (also known as c.1924G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1924. The glutamic acid at codon 642 is replaced by lysine, 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.
Invitae	RCV001047146	SCV001211083	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-03	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs752772040, gnomAD 0.003%). 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: 820348). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 642 of the PMS2 protein (p.Glu642Lys).
GeneDx	RCV001539689	SCV001757489	uncertain significance	not provided	2019-08-05	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Sema4, Sema4	RCV001013714	SCV002530241	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-10	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001539689	SCV004218968	uncertain significance	not provided	2023-02-08	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251284 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. The variant was identified along with other variants in different genes in specimens from a published study of advanced solid tumors (PMID: 29570743 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.