ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1321C>G (p.Pro441Ala)

dbSNP: rs1005538045
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001011006 SCV001171283 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-27 criteria provided, single submitter clinical testing The p.P441A variant (also known as c.1321C>G), located in coding exon 13 of the POLE gene, results from a C to G substitution at nucleotide position 1321. The proline at codon 441 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. 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.
Invitae RCV003769438 SCV002156341 uncertain significance not provided 2022-09-24 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLE protein function. ClinVar contains an entry for this variant (Variation ID: 818922). This variant has not been reported in the literature in individuals affected with POLE-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 441 of the POLE protein (p.Pro441Ala).

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