ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.6136G>A (p.Gly2046Arg) (rs1462887616)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768286 SCV000898890 uncertain significance Facial dysmorphism, immunodeficiency, livedo, and short stature 2017-10-19 criteria provided, single submitter clinical testing POLE NM_006231.3 exon 44 p.Gly2046Arg (c.6136G>A): This variant has not been reported in the literature but is present in 1/33572 Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs not available). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Invitae RCV000650796 SCV000772645 uncertain significance Colorectal cancer, susceptibility to, 12 2018-08-22 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 2046 of the POLE protein (p.Gly2046Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 44 of the POLE coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with POLE-related disease. 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: "Benign"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000760030 SCV000889780 uncertain significance not provided 2018-01-02 criteria provided, single submitter clinical testing

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