ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.6446G>A (p.Arg2149His) (rs201165149)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000474431 SCV000543953 uncertain significance Colorectal cancer, susceptibility to, 12 2019-12-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2149 of the POLE protein (p.Arg2149His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs201165149, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with POLE-related disease. ClinVar contains an entry for this variant (Variation ID: 405642). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
GeneDx RCV000479144 SCV000569082 uncertain significance not provided 2015-12-23 criteria provided, single submitter clinical testing This variant is denoted POLE c.6446G>A at the cDNA level, p.Arg2149His (R2149H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE Arg2149His was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. POLE Arg2149His occurs at a position that is not conserved and is located within the Zinc finger domains (Tahirov 2009). 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 Arg2149His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000479144 SCV001148872 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing

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