Submissions for variant NM_000535.7(PMS2):c.2069A>G (p.Lys690Arg)

dbSNP: rs876661164

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000217173	SCV000279693	uncertain significance	not provided	2015-12-11	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.2069A>G at the cDNA level, p.Lys690Arg (K690R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Lys690Arg 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 Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. PMS2 Lys690Arg occurs at a position that is conserved across species and is located in the nuclease domain (Fukui 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Lys690Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV001014304	SCV001174998	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-20	criteria provided, single submitter	clinical testing	The p.K690R variant (also known as c.2069A>G), located in coding exon 12 of the PMS2 gene, results from an A to G substitution at nucleotide position 2069. The lysine at codon 690 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is 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	RCV001854742	SCV002304015	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-06-23	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 234688). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This sequence change replaces lysine with arginine at codon 690 of the PMS2 protein (p.Lys690Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	RCV001014304	SCV004359562	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 690 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.