ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2438G>A (p.Arg813Gln) (rs587782665)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483291 SCV000566118 uncertain significance not provided 2017-02-06 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2438G>A at the cDNA level, p.Arg813Gln (R813Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in a colorectal cancer specimen (Kim 2015). PMS2 Arg813Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Arg813Gln occurs at a position that is conserved across species and is within the endonuclease domain (Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PMS2 Arg813Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000537139 SCV000625617 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-04-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 813 of the PMS2 protein (p.Arg813Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. 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 been observed in an individual affected with breast cancer (PMID: 29752822). ClinVar contains an entry for this variant (Variation ID: 418793). 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.
Ambry Genetics RCV000564658 SCV000663486 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-28 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483291 SCV001134594 uncertain significance not provided 2019-07-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000483291 SCV001155022 uncertain significance not provided 2019-04-01 criteria provided, single submitter clinical testing

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