title: Frequency of the ATM IVS10-6T-->G variant in Australian multiple-case breast cancer families.
abstract: BACKGROUND
  Germline mutations in the genes BRCA1 and BRCA2 account for only a proportion of hereditary breast cancer, suggesting that additional genes contribute to hereditary breast cancer. Recently a heterozygous variant in the ataxia-telangiectasia mutated (ATM) gene, IVS10-6T-->G, was reported by an Australian multiple-case breast cancer family cohort study (the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer) to confer a substantial breast cancer risk. Although this variant can result in a truncated ATM product, its clinical significance as a high-penetrance breast cancer allele or its role as a low-penetrance risk-modifier is controversial.
  
  
  METHODS
  We determined the frequency of ATM IVS10-6T-->G variants in a cohort of individuals affected by breast and/or ovarian cancer who underwent BRCA1 and BRCA2 genetic testing at four major Australian familial cancer clinics.
  
  
  RESULTS
  Seven of 495 patients (1.4%) were heterozygous for the IVS10-6T-->G variant; the carrier rate in unselected Australian women with no family history of breast cancer is reported to be 6 of 725 (0.83%) (P = 0.4). Two of the seven probands also harboured a pathogenic BRCA1 mutation and one patient had a BRCA1 unclassified variant of uncertain significance.
  
  
  CONCLUSIONS
  These findings indicate that the ATM IVS10-6T-->G variant does not seem to occur at a significantly higher frequency in affected individuals from high-risk families than in the general population. A role for this variant as a low-penetrance allele or as a modifying gene in association with other genes (such as BRCA1) remains possible. Routine testing for ATM IVS10-6T-->G is not warranted in mutation screening of affected individuals from high-risk families.
authors.affiliation: Familial Cancer Centre, Royal Melbourne Hospital, Melbourne, Australia. lindeman@wehi.edu.au
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Lindeman
authors.forename: Melody
authors.initials: M
authors.lastname: Hiew
authors.forename: Jane E
authors.initials: JE
authors.lastname: Visvader
authors.forename: Jennifer
authors.initials: J
authors.lastname: Leary
authors.forename: Michael
authors.initials: M
authors.lastname: Field
authors.forename: Clara L
authors.initials: CL
authors.lastname: Gaff
authors.forename: R J McKinlay
authors.initials: RJ
authors.lastname: Gardner
authors.forename: Kevin
authors.initials: K
authors.lastname: Trainor
authors.forename: Glenice
authors.initials: G
authors.lastname: Cheetham
authors.forename: Graeme
authors.initials: G
authors.lastname: Suthers
authors.forename: Judy
authors.initials: J
authors.lastname: Kirk
mesh_terms: D000328:Adult; D000368:Aged; D001260:Ataxia Telangiectasia / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D001315:Australia / Q000453:epidemiology; D001943:Breast Neoplasms / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000235:genetics*; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005260:Female; D005787:Gene Frequency / Q000235:genetics*; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006580:Genetic Carrier Screening; D005820:Genetic Testing; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012189:Retrospective Studies; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases