title: Multigene Panel Testing Detects Equal Rates of Pathogenic BRCA1/2 Mutations and has a Higher Diagnostic Yield Compared to Limited BRCA1/2 Analysis Alone in Patients at Risk for Hereditary Breast Cancer.
abstract: BACKGROUND
  Recently introduced multigene panel testing including BRCA1 and BRCA2 genes for hereditary cancer risk has raised concerns with the ability to detect all deleterious BRCA1/2 mutations compared to older methods of sequentially testing BRCA1/2 separately. The purpose of this study was to evaluate rates of pathogenic BRCA1/2 mutations and variants of uncertain significance (VUS) between previous restricted algorithms of genetic testing and newer approaches of multigene testing.
  
  
  METHODS
  Data was collected retrospectively from 966 patients who underwent genetic testing at one of three sites from a single institution. Test results were compared between patients who underwent BRCA1/2 testing only (limited group, n = 629) to those who underwent multigene testing with 5-43 cancer-related genes (panel group, n = 337).
  
  
  RESULTS
  Deleterious BRCA1/2 mutations were identified in 37 patients, with equivalent rates between limited and panel groups (4.0 vs. 3.6%, respectively, p = 0.86). Thirty-nine patients had a BRCA1/2 VUS, with similar rates between limited and panel groups (4.5 vs. 3.3%, respectively, p = 0.49). On multivariate analysis, there was no difference in detection of either BRCA1/2 mutations or VUS between both groups. Of patients undergoing panel testing, an additional 3.9 % (n = 13) had non-BRCA pathogenic mutations and 13.4% (n = 45) had non-BRCA VUSs. Mutations in PALB2, CHEK2, and ATM were the most common non-BRCA mutations identified.
  
  
  CONCLUSIONS
  Multigene panel testing detects pathogenic BRCA1/2 mutations at equivalent rates as limited testing and increases the diagnostic yield. Panel testing increases the VUS rate, mainly as a result of non-BRCA genes. Patients at risk for hereditary breast cancer can safely benefit from up-front, more efficient, multigene panel testing.
authors.affiliation: Department of Surgical Oncology, Breastlink, Orange, CA, USA, nimsikapoor@gmail.com.
authors.forename: Nimmi S
authors.initials: NS
authors.lastname: Kapoor
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Curcio
authors.forename: Carlee A
authors.initials: CA
authors.lastname: Blakemore
authors.forename: Amy K
authors.initials: AK
authors.lastname: Bremner
authors.forename: Rachel E
authors.initials: RE
authors.lastname: McFarland
authors.forename: John G
authors.initials: JG
authors.lastname: West
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Banks
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics; D064447:Checkpoint Kinase 2 / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D005810:Multigene Family; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics; D018579:Patient Selection; D057285:Precision Medicine; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human