Submissions for variant NM_004655.4(AXIN2):c.2477C>T (p.Thr826Met)

gnomAD frequency: 0.00002  dbSNP: rs759355821

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466225	SCV000548632	uncertain significance	Oligodontia-cancer predisposition syndrome	2024-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 826 of the AXIN2 protein (p.Thr826Met). 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: 408825). 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 not expected to disrupt AXIN2 protein function with a negative 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	RCV000484922	SCV000572596	uncertain significance	not provided	2019-07-24	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV001015655	SCV001176515	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-01	criteria provided, single submitter	clinical testing	The p.T826M variant (also known as c.2477C>T), located in coding exon 10 of the AXIN2 gene, results from a C to T substitution at nucleotide position 2477. The threonine at codon 826 is replaced by methionine, 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.
Sema4, Sema4	RCV001015655	SCV002537181	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-28	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484922	SCV004220135	uncertain significance	not provided	2023-08-28	criteria provided, single submitter	clinical testing	The variant has not been reported in individuals with AXIN2-related conditions in the published literature. The frequency of this variant in the general population, 0.000014 (4/282874 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics	RCV004568028	SCV005053227	uncertain significance	Colorectal cancer	2023-11-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737528	SCV005345888	uncertain significance	AXIN2-related disorder	2024-06-11	no assertion criteria provided	clinical testing	The AXIN2 c.2477C>T variant is predicted to result in the amino acid substitution p.Thr826Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/408825/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.