Submissions for variant NM_000535.7(PMS2):c.130G>C (p.Glu44Gln)

gnomAD frequency: 0.00001  dbSNP: rs786202669

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165595	SCV000216329	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-01	criteria provided, single submitter	clinical testing	The p.E44Q variant (also known as c.130G>C), located in coding exon 2 of the PMS2 gene, results from a G to C substitution at nucleotide position 130. The glutamic acid at codon 44 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000220874	SCV000279688	uncertain significance	not provided	2022-06-09	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: 22949387, 11574484)
Invitae	RCV000467663	SCV000552022	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 44 of the PMS2 protein (p.Glu44Gln). 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: 186069). 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 expected to disrupt PMS2 protein function with a positive 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.
Color Diagnostics, LLC DBA Color Health	RCV000165595	SCV000686120	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-05	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 44 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.