Submissions for variant NM_000535.7(PMS2):c.1058C>T (p.Ala353Val)

gnomAD frequency: 0.00001  dbSNP: rs543676323

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132276	SCV000187360	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	The p.A353V variant (also known as c.1058C>T), located in coding exon 10 of the PMS2 gene, results from a C to T substitution at nucleotide position 1058. The alanine at codon 353 is replaced by valine, an amino acid with 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.
Color Diagnostics, LLC DBA Color Health	RCV000132276	SCV000686093	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 353 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 6/251154 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.
Invitae	RCV000629818	SCV000750774	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 353 of the PMS2 protein (p.Ala353Val). This variant is present in population databases (rs543676323, gnomAD 0.01%). 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: 142838). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Genetic Services Laboratory, University of Chicago	RCV001818331	SCV002069438	uncertain significance	not specified	2018-08-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132276	SCV002529748	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-08	criteria provided, single submitter	curation
GeneDx	RCV002281059	SCV002569822	uncertain significance	not provided	2022-08-29	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: 22290698, 11574484)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818331	SCV002572165	uncertain significance	not specified	2022-08-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462041	SCV004205481	uncertain significance	Lynch syndrome 4	2023-08-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998139	SCV004839853	uncertain significance	Lynch syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 353 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 6/251154 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.