Submissions for variant NM_004655.4(AXIN2):c.1222G>A (p.Glu408Lys)

gnomAD frequency: 0.00004  dbSNP: rs749846538

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456551	SCV000548588	uncertain significance	Oligodontia-cancer predisposition syndrome	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 408 of the AXIN2 protein (p.Glu408Lys). This variant is present in population databases (rs749846538, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with medulloblastoma (PMID: 17373666). ClinVar contains an entry for this variant (Variation ID: 408784). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	RCV002480403	SCV000896663	uncertain significance	Oligodontia-cancer predisposition syndrome; Colorectal cancer	2022-04-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000456551	SCV001481361	uncertain significance	Oligodontia-cancer predisposition syndrome	2020-08-27	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV002255149	SCV002526552	uncertain significance	not provided	2024-09-23	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with medulloblastoma and absent in unaffected controls (PMID: 17373666); This variant is associated with the following publications: (PMID: 15735151, 17373666)
Sema4, Sema4	RCV002257715	SCV002537585	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	curation
Ambry Genetics	RCV002257715	SCV002658598	benign	Hereditary cancer-predisposing syndrome	2024-07-21	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002255149	SCV004218934	likely benign	not provided	2023-03-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004568023	SCV005053203	uncertain significance	Colorectal cancer	2024-01-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004533187	SCV004735091	uncertain significance	AXIN2-related disorder	2024-08-14	no assertion criteria provided	clinical testing	The AXIN2 c.1222G>A variant is predicted to result in the amino acid substitution p.Glu408Lys. This variant has been reported in an individual with medulloblastoma (Koch et al. 2007. PubMed ID: 17373666). This variant is reported in 0.046% of alleles in individuals of Latino descent in gnomAD. This variant has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (https://preview.ncbi.nlm.nih.gov/clinvar/variation/408784/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.