BRCA and Variant of Uncertain Clinical Significance

• When patients are told they have a variant of unknown significance (VUS):
  • It can often lead to anxiety and overtreatment
• It is important to counsel patients that a VUS:
  • Is not clinically actionable and the majority of VUS are reclassified as benign
• Patients should be counseled to update their genetic counselors:
  • As their family history changes and keep contact information up to date as variant reclassification does occur
• The American College of Medical Genetics has recommended that genetic testing classify genetic variants using the following classification schema: 
  • Deleterious (pathogenic)
  • Suspected deleterious (likely pathogenic)
  • Variant of Uncertain Clinical Significance
  • Genetic variant, favor polymorphism (likely benign)
  • Polymorphism (benign)
• While deleterious and suspected deleterious BRCA mutations:
  • Are known to be associated with an increased risk of breast and ovarian cancer:
    • Among breast cancer patients:
      • It is estimated that 2% to 6% carry a BRCA 1 / 2 mutation
    • Among epithelial ovarian cancer patients:
      • It is estimated that 10% to 15% carry a BRCA 1 / 2 mutation
    • The lifetime risk of breast cancer for BRCA 1 / BRCA 2 mutation carriers:
      • Is approximately 45% to 80%
    • The lifetime ovarian cancer risk is:
      • 45% to 60% for BRCA 1 mutation carriers
      • 11% to 35% for BRCA 2 mutation carriers
• It is unknown whether a BRCA VUS mutation:
  • Is associated with an increased risk due to limited available data
• As the use of genetic testing increases and as more of the population is tested:
  • The knowledge base regarding variant pathogenicity constantly grows
• Given the amount of data available from many years of BRCA 1 / 2 testing:
  • The prevalence of VUS among this population has declined to 2% to 5%:
    • However, among moderate and low penetrance genes:
      • The number of VUS continues to rise
• As the data expand and knowledge regarding a variant evolves:
  • A variant may be reclassified:
    • In a recent study reported in the Journal of the American Medical Association:
      • 25.4% of patients initially diagnosed with a VUS were reclassified over a 12-year period:
        • Of these patients, 97% were downgraded to benign or likely benign
        • Three percent of patients were upgraded to pathogenic or likely pathogenic variants
        • Given this low risk of reclassification to pathogenic mutation:
          • Risk-reducing mastectomy, salpingo-oophorectomy, or genetic testing of family members are not indicated for this patient
  • There is currently no established effective screening protocol for pancreatic cancer, even among patients with a deleterious BRCA 2 mutation
• References
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.
  • Hall MJ, Reid JE, Burbidge LA, Pruss D, Deffenbaugh AM, Frye C, et al. BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer. 2009;115(10):2222-2233.
  • Mersch J, Brown N, Pirzadeh-Miller S, Mundt E, Cox HC, Brown K, et al. Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA. 2018;320(12):1266-1274.

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