ClinVar Miner

Submissions for variant NM_004655.4(AXIN2):c.2239C>T (p.His747Tyr) (rs143571197)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159781 SCV000209803 uncertain significance not provided 2018-08-14 criteria provided, single submitter clinical testing This variant is denoted AXIN2 c.2239C>T at the cDNA level, p.His747Tyr (H747Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAC>TAC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. AXIN2 His747Tyr was observed at an allele frequency of 0.019% (24/126,720) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether AXIN2 His747Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000228073 SCV000288697 uncertain significance Oligodontia-colorectal cancer syndrome 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 747 of the AXIN2 protein (p.His747Tyr). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs143571197, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with AXIN2-related disease. ClinVar contains an entry for this variant (Variation ID: 182012). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Illumina Clinical Services Laboratory,Illumina RCV000228073 SCV000405680 likely benign Oligodontia-colorectal cancer syndrome 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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