Submissions for variant NM_000535.7(PMS2):c.502G>A (p.Val168Met)

gnomAD frequency: 0.00001  dbSNP: rs762645507

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165453	SCV000216183	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-10	criteria provided, single submitter	clinical testing	The p.V168M variant (also known as c.502G>A), located in coding exon 5 of the PMS2 gene, results from a G to A substitution at nucleotide position 502. The valine at codon 168 is replaced by methionine, 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 inconclusive by in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000481889	SCV000569478	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27820796, 11574484)
Color Diagnostics, LLC DBA Color Health	RCV000165453	SCV000686213	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-09	criteria provided, single submitter	clinical testing
Invitae	RCV000822639	SCV000963449	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 168 of the PMS2 protein (p.Val168Met). This variant is present in population databases (rs762645507, gnomAD 0.0009%). 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: 185940). 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.
Fulgent Genetics, Fulgent Genetics	RCV002492659	SCV002777946	uncertain significance	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2021-11-09	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000481889	SCV004026208	uncertain significance	not provided	2022-11-15	criteria provided, single submitter	clinical testing	PP3, PM2_SUP