ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.449G>A (p.Arg150Gln) (rs780775837)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000225961 SCV000289386 uncertain significance Colorectal cancer, susceptibility to, 12 2019-12-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 150 of the POLE protein (p.Arg150Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs780775837, ExAC 0.006%) but has not been reported in the literature in individuals with a POLE-related disease. ClinVar contains an entry for this variant (Variation ID: 240522). 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000235321 SCV000293722 uncertain significance not specified 2017-03-20 criteria provided, single submitter clinical testing This variant is denoted POLE c.449G>A at the cDNA level, p.Arg150Gln (R150Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE Arg150Gln 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 Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. POLE Arg150Gln occurs at a position that is conserved across species and is not located in a known functional domain (Tahirov 2009, 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 Arg150Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000562490 SCV000674328 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-19 criteria provided, single submitter clinical testing Insufficient or conflicting evidence

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