ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2867A>G (p.Tyr956Cys)

dbSNP: rs1593776406
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001756299 SCV001988529 uncertain significance not provided 2019-04-29 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV001756299 SCV003286308 uncertain significance not provided 2021-12-30 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 956 of the POLE protein (p.Tyr956Cys). This variant is not present in population databases (gnomAD no frequency). 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: 1302625). 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 disruptive. 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 RCV004945704 SCV005478872 uncertain significance Hereditary cancer-predisposing syndrome 2024-11-15 criteria provided, single submitter clinical testing The p.Y956C variant (also known as c.2867A>G), located in coding exon 25 of the POLE gene, results from an A to G substitution at nucleotide position 2867. The tyrosine at codon 956 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

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