ClinVar Miner

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

dbSNP: rs876661164
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Total submissions: 5
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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 2024-04-10 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001854742 SCV002304015 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-09-25 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 690 of the PMS2 protein (p.Lys690Arg). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. 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: 234688). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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 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.
Baylor Genetics RCV004567685 SCV005056457 uncertain significance Lynch syndrome 4 2024-01-10 criteria provided, single submitter clinical testing

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