Submissions for variant NM_000535.7(PMS2):c.14A>T (p.Glu5Val)

gnomAD frequency: 0.00001  dbSNP: rs876659080

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214871	SCV000275121	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-16	criteria provided, single submitter	clinical testing	The p.E5V variant (also known as c.14A>T), located in coding exon 1 of the PMS2 gene, results from an A to T substitution at nucleotide position 14. The glutamic acid at codon 5 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000685125	SCV000812598	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-11-30	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 5 of the PMS2 protein (p.Glu5Val). ClinVar contains an entry for this variant (Variation ID: 231310). 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.
Color Diagnostics, LLC DBA Color Health	RCV000214871	SCV000906459	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with valine at codon 5 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 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150123	SCV003837747	uncertain significance	Breast and/or ovarian cancer	2021-09-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462460	SCV004207799	uncertain significance	Lynch syndrome 4	2023-07-01	criteria provided, single submitter	clinical testing