title: Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.
abstract: BACKGROUND
  Next-generation sequencing (NGS) allows for simultaneous sequencing of multiple cancer susceptibility genes and, for an individual, may be more efficient and less expensive than sequential testing. The authors assessed the frequency of deleterious germline mutations among individuals with breast cancer who were referred for BRCA1 and BRCA2 (BRCA1/2) gene testing using a panel of 25 genes associated with inherited cancer predisposition.
  
  
  METHODS
  This was a cross-sectional study using NGS in 2158 individuals, including 1781 who were referred for commercial BRCA1/2 gene testing (cohort 1) and 377 who had detailed personal and family history and had previously tested negative for BRCA1/2 mutations (cohort 2).
  
  
  RESULTS
  Mutations were identified in 16 genes, most frequently in BRCA1, BRCA2, CHEK2, ATM, and PALB2. Among the participants in cohort 1, 9.3% carried a BRCA1/2 mutation, 3.9% carried a mutation in another breast/ovarian cancer susceptibility gene, and 0.3% carried an incidental mutation in another cancer susceptibility gene unrelated to breast or ovarian cancer. In cohort 2, the frequency of mutations in breast/ovarian-associated genes other than BRCA1/2 was 2.9%, and an additional 0.8% had an incidental mutation. In cohort 1, Lynch syndrome-related mutations were identified in 7 individuals. In contrast to BRCA1/2 mutations, neither age at breast cancer diagnosis nor family history of ovarian or young breast cancer predicted for other mutations. The frequency of mutations in genes other than BRCA1/2 was lower in Ashkenazi Jews compared with non-Ashkenazi individuals (P=.026).
  
  
  CONCLUSIONS
  Using an NGS 25-gene panel, the frequency of mutations in genes other than BRCA1/2 was 4.3%, and most mutations (3.9%) were identified in genes associated with breast/ovarian cancer.
authors.affiliation: Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nadine
authors.initials: N
authors.lastname: Tung
authors.forename: Chiara
authors.initials: C
authors.lastname: Battelli
authors.forename: Brian
authors.initials: B
authors.lastname: Allen
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kaldate
authors.forename: Satish
authors.initials: S
authors.lastname: Bhatnagar
authors.forename: Karla
authors.initials: K
authors.lastname: Bowles
authors.forename: Kirsten
authors.initials: K
authors.lastname: Timms
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
authors.forename: Christina
authors.initials: C
authors.lastname: Herold
authors.forename: Leif
authors.initials: L
authors.lastname: Ellisen
authors.forename: Jill
authors.initials: J
authors.lastname: Krejdovsky
authors.forename: Kim
authors.initials: K
authors.lastname: DeLeonardis
authors.forename: Kristin
authors.initials: K
authors.lastname: Sedgwick
authors.forename: Kathleen
authors.initials: K
authors.lastname: Soltis
authors.forename: Benjamin
authors.initials: B
authors.lastname: Roa
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wenstrup
authors.forename: Anne-Renee
authors.initials: AR
authors.lastname: Hartman
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D003430:Cross-Sectional Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D059645:Mutation Rate; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human
keywords: BRCA1; BRCA2; breast neoplasms; genetic testing; high-throughput nucleotide sequencing