Concurrent deleterious germline mutations in both BRCA1 and BRCA2 in a large series of patients. M. Martin, C. Frye, L.A. Burbidge, A.M. Deffenbaugh, D. Pruss, B.E. Ward. Myriad Genetic Laboratories, Salt Lake City, UT.
   Infrequent case reports of individuals with germline mutations in both the BRCA1 and BRCA2 genes exist but there has been no systematic analysis of prevalence in a large cohort of patients. The aim of this study was to determine the prevalence and review available personal and family history of individuals with two deleterious germline mutations. The presence of double heterozygotes (DH) was detected in patients analyzed by comprehensive sequencing of BRCA1 and BRCA2 (bidirectional sequencing of all exons, splice site junctions of both genes, plus detection of five common large rearrangements in a large proportion of patients) and in Ashkenazi Jewish (AJ) patients who underwent analysis of the three founder mutations (BRCA1 185delAG, 5385insC and BRCA2 6174delT). Of 76,825 individuals tested by full sequence analysis, 9541 patients were found to have one deleterious mutation and 26 were found to be DH (6 of whom were AJ). Of 19,673 individuals tested for only the founder mutations, 3455 patients were found to have one deleterious mutation and 33 were identified as DH. As expected, the increased incidence of mutations in the AJ population led to an increased frequency of double BRCA1 and BRCA2 heterozygotes. Within the total population of DH, 42 of the probands reported a personal history of an HBOC related cancer, including 76% with invasive breast cancer, 7% ovarian cancer and, 14% reported both breast and ovarian cancer, and 2% with DCIS. 15 of the probands reported only familial cancer history and no personal history of HBOC related cancer, and 2 specified only familial history and did not specify personal history. The reported age of diagnosis of breast cancer ranged from 22-63 years, with a mean age of 40.1. The reported age range for diagnosis of ovarian cancer was 41-88 with a mean age of 56. The clinical presentation of personal and family history does not differ significantly from individuals that carry one mutation in either the BRCA1 or BRCA2 gene suggesting that the conferred risk for cancer in DH is on the same order of magnitude as that of single mutation carriers.