ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6466G>A (p.Val2156Ile)

gnomAD frequency: 0.00001  dbSNP: rs542978638
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486198 SCV000572164 uncertain significance not provided 2016-10-31 criteria provided, single submitter clinical testing This variant is denoted POLE c.6466G>A at the cDNA level, p.Val2156Ile (V2156I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE Val2156Ile was not observed at a significant allele frequency in 1000 Genomes. Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. POLE Val2156Ile occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in 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 Val2156Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000486198 SCV001200289 uncertain significance not provided 2024-11-05 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2156 of the POLE protein (p.Val2156Ile). This variant is present in population databases (rs542978638, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 422648). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLE protein function with a negative predictive value of 80%. 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.
Ambry Genetics RCV002367648 SCV002656896 uncertain significance Hereditary cancer-predisposing syndrome 2023-10-02 criteria provided, single submitter clinical testing The p.V2156I variant (also known as c.6466G>A), located in coding exon 46 of the POLE gene, results from a G to A substitution at nucleotide position 6466. The valine at codon 2156 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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