ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4569G>A (p.Met1523Ile)

dbSNP: rs2042187083
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003541135 SCV001229448 uncertain significance not provided 2022-02-04 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 missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 858632). 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 methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1523 of the POLE protein (p.Met1523Ile).
Ambry Genetics RCV002339321 SCV002640238 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-04 criteria provided, single submitter clinical testing The p.M1523I variant (also known as c.4569G>A), located in coding exon 36 of the POLE gene, results from a G to A substitution at nucleotide position 4569. The methionine at codon 1523 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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