ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1234A>G (p.Lys412Glu) (rs587778616)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218590 SCV000274275 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-23 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient evidence;In silico models in agreement (benign)
GeneDx RCV000766288 SCV000279847 uncertain significance not provided 2016-02-02 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1234A>G at the cDNA level, p.Lys412Glu (K412E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant was identified in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old, thus the unaffected status of this individual may not be significant. In addition, PMS2 Lys412Glu 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 Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Lys412Glu occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is not located in a known functional domain (Guarne 2001, 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 Lys412Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance..
Invitae RCV000630224 SCV000751180 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2017-12-27 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 412 of the PMS2 protein (p.Lys412Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 135064). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 RCV000218590 SCV001353136 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-01 criteria provided, single submitter clinical testing
ITMI RCV000121838 SCV000086036 not provided not specified 2013-09-19 no assertion provided reference population

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