Submissions for variant NM_000535.7(PMS2):c.1551C>A (p.Ser517Arg)

gnomAD frequency: 0.00001  dbSNP: rs587782479

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131593	SCV000186606	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-18	criteria provided, single submitter	clinical testing	The p.S517R variant (also known as c.1551C>A), located in coding exon 11 of the PMS2 gene, results from a C to A substitution at nucleotide position 1551. The serine at codon 517 is replaced by arginine, an amino acid with dissimilar 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	RCV000696828	SCV000825407	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 517 of the PMS2 protein (p.Ser517Arg). This variant is present in population databases (rs587782479, gnomAD 0.004%). This missense change has been observed in individual(s) with cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 142461). 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 with a negative 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	RCV000131593	SCV001733759	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-24	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 517 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 PMS2-related disorders in the literature. This variant has been identified in 4/251270 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.
GeneDx	RCV001563355	SCV001786282	uncertain significance	not provided	2019-09-19	criteria provided, single submitter	clinical testing	Adequate data are not available in large population cohorts to assess the frequency of this variant in publicly available databases; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Mayo Clinic Laboratories, Mayo Clinic	RCV001563355	SCV004223989	uncertain significance	not provided	2022-06-02	criteria provided, single submitter	clinical testing	BP4
All of Us Research Program, National Institutes of Health	RCV003998111	SCV004844187	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 517 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 PMS2-related disorders in the literature. This variant has been identified in 4/251270 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.