Variants of uncertain significance in BRCA testing: Impact on risk perception, worry, prevention, and counseling.

Abstract

1555 Background: Genetic testing for BRCA1 and BRCA2 is an instrumental tool in clinical decision-making. Variants of uncertain significance (VUS) can occur in up to 25% of individuals and pose clinical challenges. We compared i) result recall ii) risk perception iii) worry and iv) risk modifying behaviours in individuals with VUS, a pathogenic mutation (PM) or an uninformative result (UR). Care provider attitudes to VUS were also studied. Methods: A questionnaire was mailed to women testing positive for a VUS, PM or UR. Items included demographics, time from disclosure, result recall and cancer worry using the validated Trask score. Likelihood of risk modifying behaviours or intensified screening was evaluated by 5 point Likert scale. 9 regional genetic counselors and 11 referring physicians were surveyed on VUS management. Responses were evaluated by chi square and ANOVA. Results: All groups had similar age, marital status and education. Failure to correctly identify a result as uninformative occurred in 32% of VUS; 90% had low economic status. 87% (VUS) and 44% (PMC) had personal history of breast cancer. Perceived risk increased after disclosure in 29% (VUS), 70%(PM) and 10% (UR) (p<0.001). Mean Trask scores were 7.6 (VUS) and 9.8 (PMC) (p=0.006, t-test). In affected patients, mastectomy was 22% (VUS) and 55% (PMC) (p=0.01), oophorectomy 39% (VUS) and 85% (PMCs) (p<0.001) with75% and 95% intensified screening 75% in unaffected VUS and PM (p=0.16). 3% (VUS) and 6% (PMC) agreed with chemoprophylaxis (p=NS). Genetic counselors unanimously reported low comprehension in VUS vs PM. VUS was disclosed only 75% of the time with poor comprehension, perceived anxiety and negative family history as reasons. Referring physicians recommended predictive testing for relatives of VUS carriers (100%). Conclusions: Nearly 1/3 of patients fail to recall their VUS as uninformative. Perceived risk was increased after VUS disclosure but lower than PMC. Worry scores showed impact on daily functioning. Uptake of prophylactic surgery was lower in affected VUS vs PMC carriers with similar rates of intensified screening if unaffected. Patients with low economic status or anxiety are at particular risk of incomplete counseling.