Submissions for variant NM_004655.4(AXIN2):c.2000G>A (p.Ser667Asn)

gnomAD frequency: 0.00001  dbSNP: rs878854724

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230145	SCV000288686	uncertain significance	Oligodontia-cancer predisposition syndrome	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 667 of the AXIN2 protein (p.Ser667Asn). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 240004). 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.
Fulgent Genetics, Fulgent Genetics	RCV000765384	SCV000896657	uncertain significance	Oligodontia-cancer predisposition syndrome; Carcinoma of colon	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001014047	SCV001174706	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-13	criteria provided, single submitter	clinical testing	The p.S667N variant (also known as c.2000G>A), located in coding exon 7 of the AXIN2 gene, results from a G to A substitution at nucleotide position 2000. The serine at codon 667 is replaced by asparagine, an amino acid with highly 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.
GeneDx	RCV001551935	SCV001772542	uncertain significance	not provided	2025-03-11	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed only in controls in a melanoma case control study (PMID: 29641532); This variant is associated with the following publications: (PMID: 15735151, 29641532)
Baylor Genetics	RCV003475824	SCV004213042	uncertain significance	Colorectal cancer	2024-03-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737371	SCV005346903	uncertain significance	AXIN2-related disorder	2024-07-18	no assertion criteria provided	clinical testing	The AXIN2 c.2000G>A variant is predicted to result in the amino acid substitution p.Ser667Asn. To our knowledge, this variant has not been reported in the literature in individuals affected with AXIN2-related conditions. This variant is reported in 0.0064% of alleles in individuals of African descent in gnomAD and has been interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/240004/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.