Submissions for variant NM_004655.4(AXIN2):c.1987T>C (p.Trp663Arg)

dbSNP: rs770763142

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000221915	SCV000279257	uncertain significance	not provided	2024-06-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on 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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000640210	SCV000761799	uncertain significance	Oligodontia-cancer predisposition syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 663 of the AXIN2 protein (p.Trp663Arg). This variant is present in population databases (rs770763142, gnomAD 0.0009%). 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: 234452). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Sema4, Sema4	RCV002258833	SCV002537131	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-02	criteria provided, single submitter	curation
Ambry Genetics	RCV002258833	SCV002719088	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-16	criteria provided, single submitter	clinical testing	The p.W663R variant (also known as c.1987T>C), located in coding exon 7 of the AXIN2 gene, results from a T to C substitution at nucleotide position 1987. The tryptophan at codon 663 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000221915	SCV004219209	uncertain significance	not provided	2023-05-16	criteria provided, single submitter	clinical testing	To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, 0.0000041 (1/245484 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.