ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.3548T>A (p.Ile1183Asn)

gnomAD frequency: 0.00001  dbSNP: rs1565952965
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003656377 SCV001228191 uncertain significance not provided 2023-01-19 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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) performed at Invitae indicates that this missense variant is expected to disrupt POLE protein function. ClinVar contains an entry for this variant (Variation ID: 857634). This variant has not been reported in the literature in individuals affected with POLE-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 1183 of the POLE protein (p.Ile1183Asn).
Ambry Genetics RCV002451275 SCV002616293 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-12 criteria provided, single submitter clinical testing The p.I1183N variant (also known as c.3548T>A), located in coding exon 29 of the POLE gene, results from a T to A substitution at nucleotide position 3548. The isoleucine at codon 1183 is replaced by asparagine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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