ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.1468G>A (p.Asp490Asn) (rs755463796)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000477443 SCV000544168 uncertain significance Colorectal cancer, susceptibility to, 12 2019-11-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 490 of the POLE protein (p.Asp490Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs755463796, ExAC 0.003%). This variant has not been reported in the literature in individuals with POLE-related disease. ClinVar contains an entry for this variant (Variation ID: 405843). 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 RCV000767187 SCV000572759 uncertain significance not provided 2017-01-23 criteria provided, single submitter clinical testing This variant is denoted POLE c.1468G>A at the cDNA level, p.Asp490Asn (D490N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAC>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE Asp490Asn 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 Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. POLE Asp490Asn 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 predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether POLE Asp490Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484758 SCV000601980 uncertain significance not specified 2017-05-04 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000767187 SCV001148903 uncertain significance not provided 2018-11-01 criteria provided, single submitter clinical testing

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