Submissions for variant NM_004655.4(AXIN2):c.2216A>G (p.Asn739Ser)

gnomAD frequency: 0.00004  dbSNP: rs547630327

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000456870	SCV000548608	uncertain significance	Oligodontia-cancer predisposition syndrome	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 739 of the AXIN2 protein (p.Asn739Ser). This variant is present in population databases (rs547630327, gnomAD 0.01%). 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: 408802). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	RCV000765382	SCV000896655	uncertain significance	Oligodontia-cancer predisposition syndrome; Carcinoma of colon	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001662429	SCV001874771	uncertain significance	not provided	2023-03-06	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
Sema4, Sema4	RCV002257719	SCV002537161	likely benign	Hereditary cancer-predisposing syndrome	2021-05-06	criteria provided, single submitter	curation
Ambry Genetics	RCV002257719	SCV002730849	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-25	criteria provided, single submitter	clinical testing	The p.N739S variant (also known as c.2216A>G), located in coding exon 8 of the AXIN2 gene, results from an A to G substitution at nucleotide position 2216. The asparagine at codon 739 is replaced by serine, 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.
PreventionGenetics, part of Exact Sciences	RCV003392281	SCV004119565	uncertain significance	AXIN2-related condition	2023-10-11	criteria provided, single submitter	clinical testing	The AXIN2 c.2216A>G variant is predicted to result in the amino acid substitution p.Asn739Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-63531765-T-C). It has conflicting interpretations of likely benign and uncertain significance (https://preview.ncbi.nlm.nih.gov/clinvar/variation/408802/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.