AXIN2

Gene Facts

• HGNC Symbol: AXIN2 (HGNC:904)
• HGNC Name: axin 2
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: MGC126582, DKFZp781B0869
• %HI: 4.92
• pLI: 1
• LOEUF: 0.4
• Cytoband: 17q24.1
• Genomic Coordinates:

  GRCh37/hg19:	chr17:63524681-63557766
  GRCh38/hg38:	chr17:65528563-65561648

• MANE Select Transcript: NM_004655.4 ENST00000307078.10
• Function: Inhibitor of the Wnt signaling pathway. Down-regulates beta- catenin. Probably facilitate the phosphorylation of beta-catenin and APC by GSK3B. {ECO:0000250|UniProtKB:O15169}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-14778
• ClinGen Curation ID: CCID:006725
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Assoc. with Reduced Penetrance: Uncertain
• Last Evaluated: 12/08/2021

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• oligodontia-cancer predisposition syndrome

HI Evidence

• PUBMED: 34637023
  Jensen et al. (2021): Eight family members with a likely pathogenic variant in AXIN2 that segregates with colorectal cancer (CRC), colon polyps and tooth agenesis were described. Genetic analyses were performed. Sequencing of APC, BMPR1A, ENG, EPCAM, MLH1, MSH2, MSH3, MSH6, MUTYH, NTHL1, PMS2, POLD1, POLE, PTCH1, PTEN, SCG5, SMAD4, and STK11 revealed no pathogenic variants. Authors identified a frameshift variant in AXIN2 ((NM_004655.3): c.1994dup; p.(Asn666Glnfs*41)) in 54% of 533 reads. This finding was validated by Sanger sequencing. The variant is predicted to cause a premature stop in codon 706. It has been reported twice in ClinVar and is classified as likely pathogenic.
• PUBMED: 32807118
  Macklin-Mantia et al. (2020) reported a 48yr old Female with a nasal polyp, hypodentonia, and gastric adenoma. Genetic testing identified a pathogenic variant in AXIN2, c.1822del (p.Leu608Phefs*81) (NM_004655.3). This is the first case reported in a patient with a pathogenic, germline AXIN2 variant and olfactory neuroblastoma or a gastric adenoma. These features could be part of the AXIN2 phenotype. Paternal family has a history of missing teeth and malignant cancers. One of the three children have “pegged teeth”.
• PUBMED: 30671715
  Beard et al. (2019): This case report describes a family with a nonsense variant in AXIN2 (c.1972delA, p.Ser658Alafs*31) where the three confirmed carriers presented with both oligodontia and colorectal adenomatous polyposis. The mean number of teeth missing in carriers were 16.5 (range 11–22) and mean number of polyps in carriers were 49 (range 5->100, polyps were predominantly adenomatous). The index case was referred for clinical genetic review after presenting with >100 adenomatous colonic polyps identified through colonoscopy. Testing for APC and MUTYH genes resulted with variants of unknown significance.
• PUBMED: 15042511
  Lammi et al. (2004) identified a nonsense variant in the AXIN2 gene (p.R656X) in a Finnish family in which severe permanent tooth agenesis (oligodontia) and colorectal cancer (608615) that segregated with dominant inheritance. The p.R656X variant was present in all 11 patients with oligodontia from a multigeneration family, whereas it was not present in the healthy individuals, thus showing complete segregation with the oligodontia phenotype. Lammi et al. (2004) also identified a de novo frameshift variant 1994-1995insG (causing a premature stop codon to AXIN2 exon 7) in an 13-year-old boy with severe tooth agenesis. The young age of the patient prevents the confirmation of cancer predisposition.
• PUBMED: 21416598
  Marvin et al. (2011) identified a heterozygous nonsense variant (c.1989G>A) in the AXIN2 gene in a 3-generation family (4 affected individuals) segregating autosomal dominant oligodontia variably associated with colon or gastric polyps, early-onset colorectal and/or breast cancer, and sparse hair and eyebrows. The variant was not found in 2 unaffected family members.
• PUBMED: 28195393
  Hansen et al. (2017): A frameshift variant in AXIN2 (c.1987dupT, p.Trp663Leufs*44) was identified in patient 112, who was diagnosed with CRC at age 65 and abnormal dentition was reported, consistent with Oligodontia‐colorectal cancer syndrome. This variant is not present in ExAC.

• HI Evidence Comments: Additional literature: PMID: 27696107 Rohlin et al. (2017) identified a frameshift variant in gene AXIN2 (c.254delT, p.Leu85Tyrfs*24 ) in a patient (I:55) with late onset CRC. A a synonymous variant of uncertain significance was also identified in MSH2 (c.1275A>G). Oligodontia was not present in this patient. This variant is not present in ExAC.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: There is no evidence of triplosensitivity at this time.