Steven Sorscher
Abstract
Patients are increasingly being tested for cancer-predisposing deleterious germline mutations. Identifying a BRCA germline mutation is the molecular basis for patients with the breast-ovarian cancer syndrome, the most common hereditary syndrome predisposing to breast and ovarian cancer. Like nearly all hereditary syndromes, loss of heterozygosity (LOH) is the mechanism of tumorigenesis in nearly all patients harboring a BRCA germline mutation. Roughly 7-15% of patients screened for germline BRCA mutations are instead identified as carriers of a BRCA Variant of Uncertain Significance (VUS) (1, 2). Reclassifying a VUS as either being deleterious or a benign polymorphism can take years and is typically based primarily on co-segregation studies of families whose members are identified as carrying the VUS (1,2, 3). Here, we describe a patient with an extremely strong family history suggestive of a breast cancer syndome. Her sister carried a germline BRCA VUS (R245S). Next Generation Sequencing (NGS) of our patient’s breast cancer demonstrated a low Mutation Allelic Frequency (MAF) for the same germline BRCA2 VUS, verifying no LOH for the BRCA VUS. This case underscores a particular challenge associated with germline testing of patients and NGS of tumors, both of which are becoming increasingly common. In a patient with a particular BRCA VUS and a tumor that shows a low MAF for that BRCA VUS it is reasonable to conclude that the BRCA VUS is unlikely cancer-predisposing, long before reclassification occurs. However, this case illustrates why the personal and family history should remain the gold standard in considering screening and prophylactic treatment options, even if multi-gene panel testing identifies no previously described deleterious germline mutation.