AXIN2

protein-coding

axin 2

Gene summary

The Axin-related protein, Axin2, presumably plays an important role in the regulation of the stability of beta-catenin in the Wnt signaling pathway, like its rodent homologs, mouse conductin/rat axil. In mouse, conductin organizes a multiprotein complex of APC (adenomatous polyposis of the colon), beta-catenin, glycogen synthase kinase 3-beta, and conductin, which leads to the degradation of beta-catenin. Apparently, the deregulation of beta-catenin is an important event in the genesis of a number of malignancies. The AXIN2 gene has been mapped to 17q23-q24, a region that shows frequent loss of heterozygosity in breast cancer, neuroblastoma, and other tumors. Mutations in this gene have been associated with colorectal cancer with defective mismatch repair. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004655.4

Inheritance

ClinVar variants

P:228U:2350B:1268

Top phenotype

Oligodontia-colorectal cancer syndrome

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr17:65,528,563-65,561,648

External References & Databases

Ensembl (ENSG00000168646)

Transcript & Mutation Effects

hg38 • Region Span ~33.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

oligodontia-cancer predisposition syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012075

Submitter: ClinGen

The AXIN2 protein interacts with APC and GSK3 to organize a multiprotein complex, which leads to the degradation of beta-catenin in the Wnt signaling pathway. *AXIN2* was first reported in relation to autosomal dominant oligodontia-cancer predisposition syndrome in 2004 (Lammi L et al., PMID: 15042511). Oligodontia-cancer predisposition syndrome is characterized by congenital absence of six or more permanent teeth in association with an increased risk for malignancies, ranging from gastrointestinal polyposis to early-onset colorectal cancer. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern. Therefore, the described phenotypic dental manifestations and tumor/cancer spectrum have been lumped into one disease entity: oligodontia-cancer predisposition syndrome (OMIM: 608615; MONDO: 0012075). Nine variants (missense, nonsense, and frameshift) that have been reported in 9 families in 7 publications (PMIDs: 15042511, 21416598, 23838596, 27696107, 28195393, 30671715, 34637023) were included in this curation. Co-segregation of *AXIN2* variants with disease in these families also provide additional evidence to support the gene-disease relationship. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is known to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (1.5 points). Compared to the controls, Wnt signaling was hyperactivated in the 293 cell line with an *AXIN2* truncating variant (c.2083delG) identified from patients with colorectal cancer (PMID: 11017067). Koinuma et al. observed that *AXIN2* is silenced by DNA methylation in the MSI+ (microsatellite instability) colorectal carcinoma specimens. In summary, *AXIN2* is definitively associated with autosomal dominant oligodontia-cancer predisposition syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This curation was approved by the ClinGen Hereditary Cancer GCEP on 10/27/2023 (SOP Version 9).

craniosynostosisLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0015469

Submitter: Ambry Genetics

oligodontia-cancer predisposition syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012075

Submitter: Ambry Genetics

oligodontia-cancer predisposition syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012075

Submitter: PanelApp Australia

oligodontia-cancer predisposition syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012075

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Oligodontia-colorectal cancer syndromeAD

Manifestation: Dental; Oncologic

Intervention: Oncologic

Rationale: Although the condition may be clinically recognizable in many individuals, the oncologic risk may not be clear, and awareness may allow surveillance for and early treatment of related malignancies (eg, breast cancer, colorectal cancer), which may reduce morbidity and mortality

Comments: Some individuals appear to have dental anomalies without obviously increased colorectal cancer risk

Refs: 15042511; 21626677; 21416598

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AXIN2 variants in ClinVar

18 Conditions Cataloged

Oligodontia-cancer predisposition syndromeTotal: 3386

Hereditary cancer-predisposing syndromeTotal: 2976

not providedTotal: 669

Colorectal cancerTotal: 336

not specifiedTotal: 322

AXIN2-related disorderTotal: 183

Carcinoma of colonTotal: 11

AXIN2-related attenuated familial adenomatous polyposisTotal: 11

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004655.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	995 clinvar	57 clinvar	1059
missense	1 clinvar	3 clinvar	2283 clinvar	206 clinvar	10 clinvar	2503
nonsense	41 clinvar	19 clinvar	12 clinvar			72
start loss			8 clinvar			8
frameshift	116 clinvar	23 clinvar	23 clinvar			162
splice donor/acceptor (+/-2bp)	1 clinvar	24 clinvar	17 clinvar			42
Total	159	69	2350	1201	67	3846

Highest pathogenic variant AF is 0.000020529413

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004655.4	RefSeq	NP_004646.3	10	MANE Select
ENST00000307078.10	Ensembl	ENSP00000302625.5	10	MANE Select
NM_001363813.1	RefSeq	NP_001350742.1	9	Standard
ENST00000375702.5	Ensembl	ENSP00000364854.5	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gastric cancer - Homo sapiens (human)
Cushing,s syndrome - Homo sapiens (human)
Breast cancer - Homo sapiens (human)
Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
Basal cell carcinoma - Homo sapiens (human)

Biological Process

somitogenesis
positive regulation of protein phosphorylation
intramembranous ossification
secondary heart field specification
chondrocyte differentiation involved in endochondral bone morphogenesis

Molecular Function

protein binding
beta-catenin binding
enzyme binding
ubiquitin protein ligase binding
I-SMAD binding

Cellular Component

nucleus
cytoplasm
centrosome
cytosol
beta-catenin destruction complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000307078
Coding exons: 10
Length: 33085
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125748
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0665	506	510	0.992	0.0000333	5478
Missense (PolyPhen)		124	184.17	0.67329		2122
Synonymous	-1.93	263	226	1.16	0.0000167	1679
Loss of Function	4.21	7	33.2	0.211	0.00000181	394

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000083	0.000079	rare
South Asian	0.000066	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Inhibitor of the Wnt signaling pathway. Down-regulates beta-catenin. Probably facilitate the phosphorylation of beta- catenin and APC by GSK3B (By similarity). {ECO:0000250}.;
Disease: DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:11017067}. Note=The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Oligodontia-colorectal cancer syndrome (ODCRCS) [MIM:608615]: Affected individuals manifest severe tooth agenesis and colorectal cancer or precancerous lesions of variable types. {ECO:0000269|PubMed:15042511}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.289

Intolerance Scores

LoFtool: 0.224
RVIS EVS: 0.32
RVIS percentile EVS: 72.85

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.994

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium