title: A PALB2 mutation associated with high risk of breast cancer.
abstract: BACKGROUND
  As a group, women who carry germline mutations in partner and localizer of breast cancer 2 susceptibility protein (PALB2) are at increased risk of breast cancer. Little is known about by how much or whether risk differs by mutation or family history, owing to the paucity of studies of cases unselected for family history.
  
  
  METHODS
  We screened 1,403 case probands for PALB2 mutations in a population-based study of Australian women with invasive breast cancer stratified by age at onset. The age-specific risk of breast cancer was estimated from the cancer histories of first- and second-degree relatives of mutation-carrying probands using a modified segregation analysis that included a polygenic modifier and was conditioned on the carrier case proband. Further screening for PALB2 c.3113G > A (W1038X) was conducted for 779 families with multiple cases of breast cancer ascertained through family cancer clinics in Australia and New Zealand and 764 population-based controls.
  
  
  RESULTS
  We found five independent case probands in the population-based sample with the protein-truncating mutation PALB2 c.3113G > A (W1038X); 2 of 695 were diagnosed before age 40 years and 3 of 708 were diagnosed when between ages 40 and 59 years. Both of the two early-onset carrier case probands had very strong family histories of breast cancer. Further testing found that the mutation segregated with breast cancer in these families. No c.3113G > A (W1038X) carriers were found in 764 population-based unaffected controls. The hazard ratio was estimated to be 30.1 (95% confidence interval (CI), 7.5 to 120; P < 0.0001), and the corresponding cumulative risk estimates were 49% (95% CI, 15 to 93) to age 50 and 91% (95% CI, 44 to 100) to age 70. We found another eight families carrying this mutation in 779 families with multiple cases of breast cancer ascertained through family cancer clinics.
  
  
  CONCLUSIONS
  The PALB2 c.3113G > A mutation appears to be associated with substantial risks of breast cancer that are of clinical relevance.
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria 3010, Australia. msouthey@unimelb.edu.au
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.forename: Zhi L
authors.initials: ZL
authors.lastname: Teo
authors.forename: James G
authors.initials: JG
authors.lastname: Dowty
authors.forename: Fabrice A
authors.initials: FA
authors.lastname: Odefrey
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Park
authors.forename: Marc
authors.initials: M
authors.lastname: Tischkowitz
authors.forename: Nelly
authors.initials: N
authors.lastname: Sabbaghian
authors.forename: Carmel
authors.initials: C
authors.lastname: Apicella
authors.forename: Graham B
authors.initials: GB
authors.lastname: Byrnes
authors.forename: Ingrid
authors.initials: I
authors.lastname: Winship
authors.forename: Laura
authors.initials: L
authors.lastname: Baglietto
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: David E
authors.initials: DE
authors.lastname: Goldgar
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
mesh_terms: D000328:Adult; D017668:Age of Onset; D001315:Australia; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012306:Risk; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins