ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
15042511 Lammi et al. (2004) identified an Arg656X mutation in the AXIN2 gene (p.R656X) in a Finnish family in which severe permanent tooth agenesis (oligodontia) and colorectal cancer (608615) segregated with dominant inheritance. The p.R656X mutation 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 mutation 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.
21416598 Marvin et al. (2011) identified a heterozygous nonsense mutation (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 mutation was not found in 2 unaffected family members.
28195393 Hansen et al. (2017): A frameshift mutation c.1987dupT, p.Trp663Leufs*44 in gene AXIN2 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.