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

gnomAD frequency: 0.00010  dbSNP: rs368525111

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159771	SCV000209793	uncertain significance	not provided	2023-10-25	criteria provided, single submitter	clinical testing	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)
Invitae	RCV000229079	SCV000288654	uncertain significance	Oligodontia-cancer predisposition syndrome	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 459 of the AXIN2 protein (p.Arg459His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 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. 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 Laboratory Services, Illumina	RCV000229079	SCV000405702	benign	Oligodontia-cancer predisposition 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	2022-10-21	criteria provided, single submitter	clinical testing	The p.R459H variant (also known as c.1376G>A), located in coding exon 5 of the AXIN2 gene, results from a G to A substitution at nucleotide position 1376. The arginine at codon 459 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000159771	SCV002047723	uncertain significance	not provided	2021-03-10	criteria provided, single submitter	clinical testing	The AXIN2 c.1376G>A; p.Arg459His variant (rs368525111), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 182002). This variant is found in the Finnish European population with an overall allele frequency of 0.03% (5/15530 alleles) in the Genome Aggregation Database. The arginine at codon 459 is highly conserved, but computational analyses predict that this variant is neutral (REVEL: 0.100). Due to limited information, the clinical significance of the p.Arg459His variant is uncertain at this time.
PreventionGenetics, part of Exact Sciences	RCV003422051	SCV004117960	uncertain significance	AXIN2-related condition	2023-09-03	criteria provided, single submitter	clinical testing	The AXIN2 c.1376G>A variant is predicted to result in the amino acid substitution p.Arg459His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.032% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-63533778-C-T). This variant has been interpreted as uncertain significance and benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182002/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159771	SCV004218992	uncertain significance	not provided	2022-10-11	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00032 (5/15530 chromosomes in European (Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.