ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.2377C>T (p.Arg793Cys) (rs376624527)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000476832 SCV000544062 uncertain significance Colorectal cancer, susceptibility to, 12 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 793 of the POLE protein (p.Arg793Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs376624527, ExAC 0.01%). This variant has not been reported in the literature in individuals with POLE-related disease. ClinVar contains an entry for this variant (Variation ID: 405741). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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 RCV000478556 SCV000572554 uncertain significance not provided 2016-12-28 criteria provided, single submitter clinical testing This variant is denoted POLE c.2377C>T at the cDNA level, p.Arg793Cys (R793C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). 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 gastric carcinoma (COSMIC) and in a brain tumor from an individual who harbored a germline pathogenic POLE variant (Johanns 2016). POLE Arg793Cys was not observed at significant allele frequency in the NHLBI Exome Sequencing Project. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. POLE Arg793Cys occurs at a position that is conserved across species and is located in the Polymerase domain (Preston 2010). 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 POLE Arg793Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000478556 SCV001148897 uncertain significance not provided 2017-01-01 criteria provided, single submitter clinical testing

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