Submissions for variant NM_004655.4(AXIN2):c.-12_8del (p.Met1fs)

dbSNP: rs768265778

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159783	SCV000209805	uncertain significance	not provided	2024-10-21	criteria provided, single submitter	clinical testing	Deletion involving the initiation codon in a gene for which a downstream in-frame ATG could serve as an alternate initiator codon; Observed in an individual with breast cancer (PMID: 26681312); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15611123, 26681312, 36502525)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228766	SCV000288634	uncertain significance	Oligodontia-cancer predisposition syndrome	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the AXIN2 mRNA. The next in-frame methionine is located at codon 5. This variant is present in population databases (rs768265778, gnomAD 0.007%). Disruption of the initiator codon has been observed in individual(s) with clinical features of AXIN2-related conditions (PMID: 26681312, 36502525). ClinVar contains an entry for this variant (Variation ID: 239971). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001640382	SCV001519371	pathogenic	Oligodontia-cancer predisposition syndrome; AXIN2-related attenuated familial adenomatous polyposis	2021-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000159783	SCV002048138	uncertain significance	not provided	2020-12-26	criteria provided, single submitter	clinical testing	The AXIN2 c.-12_8del; p.Met1? variant (rs768265778) is reported in the literature in at least one individual affected with breast cancer (Susswein 2016). This variant is also reported in ClinVar (Variation ID: 239971), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes loss of the canonical initiator methionine codon by deleting 12 nucleotides upstream of the ATG start site and 8 nucleotides of the coding region. While this variant is predicted to disrupt protein translation from the normal start site, there is an alternate in-frame methionine located just downstream. However, without functional studies, the effect of this variant on translation is unknown. Due to limited information, the clinical significance of the c.-12_8del; p.Met1? variant is uncertain at this time. References: Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32.
Ambry Genetics	RCV002347889	SCV002642973	uncertain significance	Hereditary cancer-predisposing syndrome	2025-01-02	criteria provided, single submitter	clinical testing	The c.-12_8del20 variant (also known as p.M1?) is located in coding exon 1 of the AXIN2 gene and results from a deletion of 20 nucleotides at positions c.-12 to c.8. This removes the methionine residue at the initiation codon. This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med., 2016 08;18:823-32). This variant has been reported in a French family with oligodontia (Leclerc J et al. Genes Chromosomes Cancer. 2023 Apr;62(4):210-222). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with AXIN2-related disease but also in unaffected individuals (Ambry internal data). Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an alternate in-frame methionine 4 amino acids from the initiation site, which may result in N-terminal truncation of unknown significance. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003475820	SCV004210754	uncertain significance	Colorectal cancer	2024-03-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000159783	SCV005432408	uncertain significance	not provided	2024-11-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159783	SCV005624983	uncertain significance	not provided	2023-12-05	criteria provided, single submitter	clinical testing	The AXIN2 c.-12_8del variant disrupts the translation initiation codon of the AXIN2 mRNA and is predicted to interfere with AXIN2 protein synthesis, however there is alternate in-frame methionine located downstream at the 5th codon that results in a biologically relevant transcript. In the published literature, this variant has been reported in individuals with colorectal polyps and intestinal cancer (PMID: 36502525 (2022)) and breast cancer (PMID: 26681312 (2015)). The frequency of this variant in the general population, 0.0000083 (2/241688 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.