What are the indications for BRCA (Breast Cancer Gene) testing?

Indications for BRCA Gene Testing

BRCA genetic testing should be offered to individuals with specific personal or family history characteristics that suggest an increased likelihood of carrying harmful BRCA1/2 mutations, including early-onset breast cancer, multiple affected family members, and Ashkenazi Jewish ancestry. 1

Personal History Indications

• Breast cancer diagnosed at or before age 50 1
• Triple-negative breast cancer diagnosed at or before age 60 1
• Two or more primary breast cancers in the same individual 1
• Ovarian, fallopian tube, or primary peritoneal cancer at any age 1
• Male breast cancer at any age 1
• Pancreatic cancer at any age with Ashkenazi Jewish ancestry 1
• Metastatic or high-risk prostate cancer (Gleason score ≥7) 1

Family History Indications

• First-degree relative with breast cancer diagnosed at or before age 50 1, 2
• Three or more cases of breast, ovarian, pancreatic, and/or aggressive prostate cancer in close relatives 1
• First-degree relative with ovarian, fallopian tube, or primary peritoneal cancer 1
• First-degree relative with male breast cancer 1
• Two or more relatives with breast cancer, with one diagnosed before age 50 1
• Family history of known BRCA1 or BRCA2 mutation 1, 3
• Two or more cases of prostate cancer diagnosed before age 55 in close relatives 1
• Three or more first-degree relatives with prostate cancer 1

Ancestry-Based Indications

• Ashkenazi Jewish ancestry with breast or pancreatic cancer at any age 1
• Ashkenazi Jewish ancestry with a family history of breast, ovarian, or pancreatic cancer 4

Testing Approach

1. Begin with affected family member when possible

   • Testing should ideally start with a family member who has had breast or ovarian cancer 1, 3
   • If no affected relative is available, testing the unaffected individual is reasonable 1

2. Testing methodology

   • For Ashkenazi Jewish individuals, initial testing for the three founder mutations 3
   • For individuals without known mutations in family or ethnic group, comprehensive sequencing 1
   • Include testing for large genomic alterations (duplications/deletions) 1

Risk Assessment Before Testing

• Use validated risk assessment tools to identify candidates for testing:

  • Ontario Family History Assessment Tool
  • Manchester Scoring System
  • Referral Screening Tool (B-RST)
  • Pedigree Assessment Tool
  • Family History Screen-7 3

• General breast cancer risk models (e.g., Gail model) should not be used to determine need for genetic testing 3

Important Considerations and Pitfalls

• Meeting multiple criteria significantly increases likelihood of finding a mutation

  • Meeting only one criterion may have a positive predictive value as low as 3.2% 5
  • Meeting multiple criteria increases positive predictive value to approximately 12% 5

• Pre-test genetic counseling is essential

  • Should include detailed family history analysis, risk assessment, education about possible results and implications 1, 3
  • Discussion of screening and risk-reduction options 1

• Interpretation of negative results requires caution

  • A true negative result (no mutation in someone whose family has a known mutation) generally indicates population-level risk 1
  • An uninformative negative result (no mutation found but family mutation status unknown) may still indicate increased risk 1
  • Variants of uncertain significance (VUS) should not guide clinical management 1, 3

• Testing should begin at age 18 or older (age of consent) 1

• Periodic reassessment of family history is recommended (every 5-10 years) 1

BRCA testing should only be performed when results will aid in medical decision-making and when the individual has access to a health professional trained to provide genetic counseling and interpret test results 1.