title: Comprehensive sequencing of PALB2 in patients with breast cancer suggests PALB2 mutations explain a subset of hereditary breast cancer.
abstract: BACKGROUND
  This study sought to determine the prevalence of PALB2 mutations in a cohort referred for diagnostic testing for hereditary breast cancer.
  
  
  METHODS
  Sanger sequencing was used to analyze the entire coding region and flanking introns of PALB2 in anonymized DNA samples from 1479 patients. Samples were stratified into a "high-risk" group, 955 samples from individuals predicted to have a high probability of carrying a mutation in BRCA1 or BRCA2 based on their personal and family history, and a "lower-risk" group consisting of 524 samples from patients with breast cancer, but fewer risk factors for being a BRCA1 or BRCA2 mutation carrier. All patients were known to be negative for deleterious sequence mutations and large rearrangements in BRCA1 and BRCA2.
  
  
  RESULTS
  We identified 12 disease-associated PALB2 mutations among the 1479 patients (0.8%). The PALB2 mutations included 8 nonsense, 3 frameshift mutations and a splice-site mutation. The mutation prevalence for the high-risk population was 1.05% (95% CI = 0.5-1.92), whereas that for the lower-risk population was 0.38% (95% CI = 0.05-1.37). We identified 59 PALB2 variants of uncertain significance (VUS) among 57 of the 1479 patients (3.9%).
  
  
  CONCLUSIONS
  These results suggest that PALB2 mutations occur at a frequency of ~1% in patients with hereditary breast cancer.
authors.affiliation: Myriad Genetic Laboratories, Inc., Salt Lake City, Utah.
authors.forename: Priscilla H
authors.initials: PH
authors.lastname: Fernandes
authors.forename: Jennifer
authors.initials: J
authors.lastname: Saam
authors.forename: Jenny
authors.initials: J
authors.lastname: Peterson
authors.forename: Elisha
authors.initials: E
authors.lastname: Hughes
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kaldate
authors.forename: Shelly
authors.initials: S
authors.lastname: Cummings
authors.forename: Aaron
authors.initials: A
authors.lastname: Theisen
authors.forename: Sonia
authors.initials: S
authors.lastname: Chen
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Trost
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Roa
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D018567:Breast Neoplasms, Male / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015995:Prevalence; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004273:DNA, Neoplasm; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins
keywords: BRCA1; BRCA2; PALB2; hereditary breast cancer; mutation; sequencing