- 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 variantbreclassification 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
- Favor polymorphism:
- Polymorphism:
- Benign
- Has recommended that genetic testing classify genetic variants using the following classification schema:
- While deleterious and suspected deleterious mutations 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
- It is unknown whether a BRCA VUS mutation:
- Are known to be associated with an increased risk of breast and ovarian cancer:
- 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.
- The number of VUS continues to rise:
- However, among moderate and low penetrance genes:
- The prevalence of VUS among this population has declined to 2% to 5%:
- 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 (3%):
- Were upgraded to pathogenic or likely pathogenic variants
- Of these patients:
- 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
- 25.4% of patients initially diagnosed with a VUS were reclassified over a 12-year period:
- 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.
Rodrigo Arrangoiz MS, MD, FACS, FSSO 