Variant of Unknown Significance (VUS) In Hereditary Breast Cancer Tests

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • 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 mutations of BRCA mutations:
    • Are known to be associated with an increased risk of breast and ovarian cancer:
      • 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 BRCA1 / BRCA 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 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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Published by Rodrigo Arrangoiz MS, MD, FACS, FSSO

My name is Rodrigo Arrangoiz I am a breast surgeon/ thyroid surgeon / parathyroid surgeon / head and neck surgeon / surgical oncologist that works at Center for Advanced Surgical Oncology in Miami, Florida. I was trained as a surgeon at Michigan State University from (2005 to 2010) where I was a chief resident in 2010. My surgical oncology and head and neck training was performed at the Fox Chase Cancer Center in Philadelphia from 2010 to 2012. At the same time I underwent a masters in science (Clinical research for health professionals) at the University of Drexel. Through the International Federation of Head and Neck Societies / Memorial Sloan Kettering Cancer Center I performed a two year head and neck surgery and oncology / endocrine fellowship that ended in 2016. Mi nombre es Rodrigo Arrangoiz, soy cirujano oncólogo / cirujano de tumores de cabeza y cuello / cirujano endocrino que trabaja Center for Advanced Surgical Oncology en Miami, Florida. Fui entrenado como cirujano en Michigan State University (2005 a 2010 ) donde fui jefe de residentes en 2010. Mi formación en oncología quirúrgica y e n tumores de cabeza y cuello se realizó en el Fox Chase Cancer Center en Filadelfia de 2010 a 2012. Al mismo tiempo, me sometí a una maestría en ciencias (investigación clínica para profesionales de la salud) en la Universidad de Drexel. A través de la Federación Internacional de Sociedades de Cabeza y Cuello / Memorial Sloan Kettering Cancer Center realicé una sub especialidad en cirugía de cabeza y cuello / cirugia endocrina de dos años que terminó en 2016.

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