ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2247T>A (p.Asn749Lys)

dbSNP: rs200824831
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165433 SCV000216162 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-24 criteria provided, single submitter clinical testing The p.N749K variant (also known as c.2247T>A), located in coding exon 13 of the PMS2 gene, results from a T to A substitution at nucleotide position 2247. The asparagine at codon 749 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000461355 SCV000552021 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-11-10 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 749 of the PMS2 protein (p.Asn749Lys). 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: 185928). 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 expected to disrupt PMS2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PMS2 function (PMID: 35451539). 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.
GeneDx RCV000759199 SCV000569315 uncertain significance not provided 2016-12-05 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2247T>A at the cDNA level, p.Asn749Lys (N749K) at the protein level, and results in the change of an Asparagine to a Lysine (AAT>AAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Asn749Lys 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 Asparagine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Asn749Lys occurs at a position that is conserved across species and is located within the nuclease domain (Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Asn749Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759199 SCV000888402 uncertain significance not provided 2018-04-27 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000165433 SCV002530275 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-29 criteria provided, single submitter curation
Myriad Genetics, Inc. RCV003454404 SCV004187595 likely pathogenic Lynch syndrome 4 2023-09-22 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 35451539]. This variant is expected to disrupt protein structure [Myriad internal data].
Baylor Genetics RCV003454404 SCV004205494 uncertain significance Lynch syndrome 4 2023-08-03 criteria provided, single submitter clinical testing

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