Clinical Decision-Making in Patients with Variant of Uncertain Significance in BRCA1 or BRCA2 Genes

How diagnosis with a variant of uncertain significance (VUS) in a BRCA gene impacts clinical decision-making is not well known.

We queried for all patients attending Mayo Clinic Rochester from 2004 to 2016 who tested positive for BRCA1 or BRCA2 VUS and reviewed patient management choices. Groups were compared by using Wilcoxon rank-sum and Chi-square tests.

We identified 97 patients (95 females, 2 males) with BRCA VUS. For patients without cancer history (n = 20), 80% had a mother or sister with breast cancer, and median Tyrer-Cuzick (IBIS) lifetime breast cancer risk score was 27% (range 16-62%). Management included bilateral prophylactic mastectomy (BPM) in 39%, where choice for BPM was significantly associated with IBIS score (median 32 vs. 24%, p = 0.02) and first-degree family history of breast cancer (100 vs. 64%, p = 0.03) but not Gail score or total number of family members with cancer. For patients with breast cancer who had known VUS status prior to surgery (n = 9), the rate of contralateral prophylactic mastectomy (CPM) was 22% compared with 25% without known VUS and 83% with known BRCA pathogenic mutation. In 21 of 97 (22%) patients, the BRCA VUS has been reclassified (95% benign, 5% deleterious).

BRCA VUS carriers with cancer elected surgical choices similar to average-risk breast cancer patients. However, VUS carriers without cancer had high rates of BPM, associated with first-degree family history and IBIS score. Over time, a significant proportion of BRCA VUS were reclassified, illustrating the importance of appropriate counseling regarding VUS.