ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2247T>A (p.Asn749Lys) (rs200824831)

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Total submissions: 4
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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 2019-03-20 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000461355 SCV000552021 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 749 of the PMS2 protein (p.Asn749Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. 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 variant has not been reported in the literature in individuals with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 185928). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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

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