Submissions for variant NM_004655.4(AXIN2):c.1397C>T (p.Ser466Phe)

dbSNP: rs1064793954

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485659	SCV000567447	uncertain significance	not provided	2018-04-17	criteria provided, single submitter	clinical testing	This variant is denoted AXIN2 c.1397C>T at the cDNA level, p.Ser466Phe (S466F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCC>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. AXIN2 Ser466Phe was not observed in large population cohorts (Lek 2016). This variant is located in the beta catenin binding domain (Salahshor 2005). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether AXIN2 Ser466Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547684	SCV000639090	uncertain significance	Oligodontia-cancer predisposition syndrome	2024-09-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 466 of the AXIN2 protein (p.Ser466Phe). This variant is not present in population databases (gnomAD no frequency). 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: 419561). 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 expected to disrupt AXIN2 protein function with a positive 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.
Ambry Genetics	RCV002395152	SCV002701698	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-12	criteria provided, single submitter	clinical testing	The p.S466F variant (also known as c.1397C>T), located in coding exon 5 of the AXIN2 gene, results from a C to T substitution at nucleotide position 1397. The serine at codon 466 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is conserved. 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.
PreventionGenetics, part of Exact Sciences	RCV004527585	SCV004111357	uncertain significance	AXIN2-related disorder	2023-01-17	criteria provided, single submitter	clinical testing	The AXIN2 c.1397C>T variant is predicted to result in the amino acid substitution p.Ser466Phe. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.