Are there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors

Am J Hum Genet. 1999 Oct;65(4):995-1006. doi: 10.1086/302575.


We have analyzed a panel of 14 cases of childhood adrenocortical tumors unselected for family history and have identified germline TP53 mutations in >80%, making this the highest known incidence of a germline mutation in a tumor-suppressor gene in any cancer. The spectrum of germline TP53 mutations detected is remarkably limited. Analysis of tumor tissue for loss of constitutional heterozygosity, with respect to the germline mutant allele and the occurrence of other somatic TP53 mutations, indicates complex sequences of genetic events in a number of tumors. None of the families had cancer histories that conformed to the criteria for Li-Fraumeni syndrome, but, in some families, we were able to demonstrate that the mutation had been inherited. In these families there were gene carriers unaffected in their 40s and 50s, and there were others with relatively late-onset cancers. These data provide evidence that certain TP53 alleles confer relatively low penetrance for predisposition to the development of cancer, and they imply that deleterious TP53 mutations may be more frequent in the population than has been estimated previously. Our findings have considerable implications for the clinical management of children with andrenocortical tumors and their parents, in terms of both genetic testing and the early detection and treatment of tumors.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adolescent
  • Adrenal Cortex Neoplasms / diagnosis
  • Adrenal Cortex Neoplasms / epidemiology
  • Adrenal Cortex Neoplasms / genetics*
  • Adrenal Cortex Neoplasms / metabolism
  • Adult
  • Age of Onset
  • Aged
  • Alleles*
  • Carrier Proteins
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • DNA-Binding Proteins*
  • Female
  • Genes, p53 / genetics*
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing
  • Germ-Line Mutation / genetics
  • Humans
  • Immunohistochemistry
  • Li-Fraumeni Syndrome / genetics
  • Loss of Heterozygosity / genetics
  • Male
  • Microsatellite Repeats / genetics
  • Middle Aged
  • Molecular Sequence Data
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • Neoplasm Proteins / analysis
  • Nuclear Proteins
  • Penetrance*
  • Polymorphism, Single-Stranded Conformational
  • Proto-Oncogene Proteins / analysis


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA-Binding Proteins
  • MLH1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein

Associated data

  • OMIM/201300