ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2128G>A (p.Glu710Lys) (rs1060503131)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000472884 SCV000552003 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-06-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 710 of the PMS2 protein (p.Glu710Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in the population databases (ExAC no frequency). However, the frequency data is considered unreliable due to the presence of a pseudogene that has strong homology to this region. This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 411051). 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 RCV000486883 SCV000565767 uncertain significance not provided 2016-09-26 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2128G>A at the cDNA level, p.Glu710Lys (E710K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Glu710Lys 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 Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Glu710Lys occurs at a position that is conserved across species and is located in the endonuclease motif within the endonuclease domain (Kosinski 2008, 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 Glu710Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572286 SCV000670758 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-07 criteria provided, single submitter clinical testing Insufficient or conflicting evidence

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