BACKGROUND AND PURPOSE: 

• Manickam et al. (JAMA Network Open, 2018) sought to identify significant disease-causing BRCA1/2 variants and their associated features

METHODS: 

• Cross-sectional study of adult volunteers who underwent exome sequencing at a single health care system 
• Participants underwent sequencing and return of actionable test results 
  • Pathogenic and likely pathogenic (P/LP) variants  
• Clinical data from electronic health records and clinical visits were correlated with variants 
• Comparisons were made between those with P/LP variants in BRCA1/2 (cases) and those without (controls)

RESULTS: 

• 50,726 participants were included in the study  
  • 50,459 (99.5%) had no expected pathogenic BRCA1/2 variants 
  • 267 (0.5%) were BRCA1/2 carriers 
  • 148 [55.4%] were women 
  • 183 (68.5%) received clinically confirmed results in their electronic health record 
• Among the 267 participants with P/LP BRCA1/2 variants 
  • 219 (82.0%) had no prior clinical testing 
  • 95 (35.6%) had BRCA1 variants 
  • 172 (64.4%) had BRCA2 variants 
  • 56 (20.9%) had syndromic cancer diagnoses  
• Among women, personal history of breast cancer was present in 
  • Variant carriers: 31/148 (20.9%)  
  • Noncarriers: 1554/29,880 (5.2%)  
  • Odds ratio (OR), 5.95 (95% CI, 3.88-9.13; P < .001) 
• Among women, ovarian cancer history was present in 
  • Variant carriers: 15/148 (10.1%)  
  • Noncarriers: 195/29,880 (0.6%)  
  • OR 18.30 (95% CI, 10.48-31.4; P < .001) 
• Among 89 BRCA1/2 carriers without prior testing, 44 (49.4%) did not meet published (NCCN) guidelines for clinical testing

CONCLUSION: 

• Compared with previous clinical care, exome sequencing–based screening identified 5 times as many individuals with P/LP BRCA1/2 variants 
• Only 17.9% of BRCA1/2 carriers had BRCA1/2 testing as part of their health care 
• Genomic screening may identify BRCA1/2-associated cancer risk that might otherwise remained undetected 
• The authors state 

The prevalence of BRC1/2 variants in the general population may be substantially higher than was previously estimated, and reliance on personal and family history may be an inadequate measure to ascertain risk for BRCA1/2 variants. 

Learn More – Primary Sources: 

Exome Sequencing–Based Screening for BRCA1/2 Expected Pathogenic Variants Among Adult Biobank Participants

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