ClinVar Miner

Submissions for variant NM_004655.4(AXIN2):c.1420C>T (p.His474Tyr)

gnomAD frequency: 0.00001  dbSNP: rs1060502132
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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 RCV000469614 SCV000548584 uncertain significance Oligodontia-cancer predisposition syndrome 2024-11-21 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 474 of the AXIN2 protein (p.His474Tyr). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with AXIN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 408780). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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 RCV002393117 SCV002697340 uncertain significance Hereditary cancer-predisposing syndrome 2024-10-17 criteria provided, single submitter clinical testing The p.H474Y variant (also known as c.1420C>T), located in coding exon 5 of the AXIN2 gene, results from a C to T substitution at nucleotide position 1420. The histidine at codon 474 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is not well 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.
GeneDx RCV003236803 SCV003935831 uncertain significance not provided 2022-12-23 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15735151)
Baylor Genetics RCV003476068 SCV004213035 uncertain significance Colorectal cancer 2023-09-11 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000469614 SCV005689246 uncertain significance Oligodontia-cancer predisposition syndrome 2024-08-09 criteria provided, single submitter clinical testing The AXIN2 c.1420C>T (p.His474Tyr) missense change has a maximum subpopulation frequency of 0.007% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with oligodontia-cancer predisposition syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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