The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases

Am J Hum Genet. 1997 Nov;61(5):1036-43. doi: 10.1086/301607.


Cowden syndrome (CS) is an autosomal dominant disorder associated with the development of hamartomas and benign tumors in a variety of tissues, including the skin, thyroid, breast, endometrium, and brain. It has been suggested that women with CS are at increased risk for breast cancer. A locus for CS was recently defined on chromosome 10 in 12 families, resulting in the identification of the CS critical interval, between the markers D10S215 and D10S541. More recently, affected individuals in four families with CS have been shown to have germ-line mutations in a gene known as "PTEN," or "MMAC1," which is located in the CS critical interval on chromosome 10. In this study, we report three novel MMAC1 mutations in CS and demonstrate that MMAC1 mutations are associated with CS and breast cancer. Furthermore, we also show that certain families and individuals with CS do not have mutations in the coding sequence of MMAC1. Finally, we did not detect MMAC1 mutations in a subpopulation of individuals with early-onset breast cancer, suggesting that germ-line mutations in this gene do not appear to be common in this group.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Breast Neoplasms / genetics*
  • Chromosomes, Human, Pair 10 / genetics
  • Female
  • Genes, BRCA1*
  • Genes, Dominant
  • Genetic Markers / genetics
  • Hamartoma Syndrome, Multiple / genetics*
  • Haplotypes / genetics
  • Humans
  • Lod Score
  • Male
  • Mutation
  • PTEN Phosphohydrolase
  • Pedigree
  • Phosphoric Monoester Hydrolases*
  • Polymerase Chain Reaction
  • Protein Tyrosine Phosphatases / genetics*
  • Risk Factors
  • Sequence Analysis, DNA
  • Tumor Suppressor Proteins*


  • Genetic Markers
  • Tumor Suppressor Proteins
  • Phosphoric Monoester Hydrolases
  • Protein Tyrosine Phosphatases
  • PTEN Phosphohydrolase
  • PTEN protein, human