ClinVar Miner

Submissions for variant NM_004655.4(AXIN2):c.1376G>A (p.Arg459His) (rs368525111)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159771 SCV000209793 uncertain significance not provided 2017-12-18 criteria provided, single submitter clinical testing This variant is denoted AXIN2 c.1376G>A at the cDNA level, p.Arg459His (R459H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. AXIN2 Arg459His was observed at an allele frequency of 0.006% (2/30,822) in large population cohorts (Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. AXIN2 Arg459His is located in the beta-catenin binding domain (Salahshor 2005). 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 Arg459His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000229079 SCV000288654 uncertain significance Oligodontia-colorectal cancer syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 459 of the AXIN2 protein (p.Arg459His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs368525111, ExAC 0.01%). This variant has not been reported in the literature in individuals with a AXIN2-related disease. ClinVar contains an entry for this variant (Variation ID: 182002). 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, this variant has uncertain impact on AXIN2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV000229079 SCV000405702 benign Oligodontia-colorectal cancer syndrome 2018-01-13 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Ambry Genetics RCV001011231 SCV001171529 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-06 criteria provided, single submitter clinical testing Insufficient evidence

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.