Submissions for variant NM_000535.7(PMS2):c.1857C>A (p.Asp619Glu)

dbSNP: rs876661271

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000215622	SCV000279947	uncertain significance	not provided	2016-03-02	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.1857C>A at the cDNA level, p.Asp619Glu (D619E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAC>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Asp619Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Glutamic Acid share similar properties, this is considered a conservative amino acid substitution. PMS2 Asp619Glu occurs at a position that is not conserved and is not located in a known functional domain (Fukui 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 Asp619Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV001069181	SCV001234333	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 619 of the PMS2 protein (p.Asp619Glu). 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: 234875). 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.
Ambry Genetics	RCV002408940	SCV002724053	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-23	criteria provided, single submitter	clinical testing	The p.D619E variant (also known as c.1857C>A), located in coding exon 11 of the PMS2 gene, results from a C to A substitution at nucleotide position 1857. The aspartic acid at codon 619 is replaced by glutamic acid, an amino acid with highly similar 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.
Color Diagnostics, LLC DBA Color Health	RCV002408940	SCV004359583	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 619 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 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.