ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1264C>T (p.His422Tyr)

gnomAD frequency: 0.00004  dbSNP: rs745356467
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000486455 SCV000289247 uncertain significance not provided 2024-11-27 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 422 of the POLE protein (p.His422Tyr). This variant is present in population databases (rs745356467, gnomAD 0.01%). This missense change has been observed in individual(s) with endometrial cancer (PMID: 26763250). ClinVar contains an entry for this variant (Variation ID: 240384). 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 expected to disrupt POLE protein function with a positive 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.
GeneDx RCV000486455 SCV000571263 uncertain significance not provided 2024-03-13 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29056344, 25124163, 20951805, 11988770, 26763250)
Ambry Genetics RCV000571029 SCV000671508 uncertain significance Hereditary cancer-predisposing syndrome 2024-05-13 criteria provided, single submitter clinical testing The p.H422Y variant (also known as c.1264C>T), located in coding exon 13 of the POLE gene, results from a C to T substitution at nucleotide position 1264. The histidine at codon 422 is replaced by tyrosine, an amino acid with similar properties. This alteration has been identified in an individual with endometrial cancer (McConechy M et al. Clin. Cancer Res. 2016 06;22(12):2865-73). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Sema4, Sema4 RCV000571029 SCV002538600 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-21 criteria provided, single submitter curation
Baylor Genetics RCV004567754 SCV005056542 uncertain significance Colorectal cancer, susceptibility to, 12 2024-02-29 criteria provided, single submitter clinical testing

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