title: Mutation analysis of FANCD2, BRIP1/BACH1, LMO4 and SFN in familial breast cancer.
abstract: BACKGROUND
  Mutations in known predisposition genes account for only about a third of all multiple-case breast cancer families. We hypothesized that germline mutations in FANCD2, BRIP1/BACH1, LMO4 and SFN may account for some of the unexplained multiple-case breast cancer families.
  
  
  METHODS
  The families used in this study were ascertained through the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab). Denaturing high performance liquid chromatography (DHPLC) analysis of the coding regions of these four genes was conducted in the youngest affected cases of 30 to 267 non-BRCA1/2 breast cancer families. In addition, a further 399 index cases were also screened for mutations in two functionally significant regions of the FANCD2 gene and 253 index cases were screened for two previously reported mutations in BACH1 (p. P47A and p. M299I).
  
  
  RESULTS
  DHPLC analysis of FANCD2 identified six silent exonic variants, and a large number of intronic variants, which tagged two common haplotypes. One protein truncating variant was found in BRIP1/BACH1, as well as four missense variants, a silent change and a variant in the 3' untranslated region. No missense or splice site mutations were found in LMO4 or SFN. Analysis of the missense, silent and frameshift variants of FANCD2 and BACH1 in relatives of the index cases, and in a panel of controls, found no evidence suggestive of pathogenicity.
  
  
  CONCLUSIONS
  There is no evidence that highly penetrant exonic or splice site mutations in FANCD2, BRIP1/BACH1, LMO4 or SFN contribute to familial breast cancer. Large scale association studies will be necessary to determine whether any of the polymorphisms or haplotypes identified in these genes contributes to breast cancer risk.
authors.affiliation: Department of Cancer Genetics, Queensland Institute of Medical Research, Brisbane, Queensland, Australia. aaronL@qimr.edu.au
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Lewis
authors.forename: James
authors.initials: J
authors.lastname: Flanagan
authors.forename: Anna
authors.initials: A
authors.lastname: Marsh
authors.forename: Gulietta M
authors.initials: GM
authors.lastname: Pupo
authors.forename: Graham
authors.initials: G
authors.lastname: Mann
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Spurdle
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Lindeman
authors.forename: Jane E
authors.initials: JE
authors.lastname: Visvader
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Brown
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
mesh_terms: D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D017668:Age of Onset; D000368:Aged; D017398:Alternative Splicing; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D005092:Exonucleases / Q000235:genetics; D005095:Exoribonucleases; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics; D051856:Fanconi Anemia Complementation Group Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D060588:LIM Domain Proteins; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D010375:Pedigree; D020365:RNA Helicases / Q000235:genetics; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics
chemical_list: D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; C114905:LMO4 protein, human; D009363:Neoplasm Proteins; D014157:Transcription Factors; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human; C000618935:BRIP1 protein, human; D020365:RNA Helicases