Probability of Detecting Mutations in BRCA1 or BRCA2

The probability of detecting a BRCA mutation in a given individual varies greatly with the clinical scenario. In two population-based series of unselected breast cancer cases, the rate of BRCA1 mutation was 2.6% overall and 6.2% in women affected before the age of 35 (2.9% if the young woman had no family history of breast cancer). Although no BRCA1 mutations were found among women of African descent in these series, several groups have observed mutations among African-American families presenting to cancer risk assessment clinics.

Population-based prevalence data are not currently available for BRCA2, but the contribution to early-onset breast cancer appears to be less than that of BRCA1. In one series, only 2.7% of women with breast cancer at or before age 32 were found to have BRCA2 mutations. In part, this under-representation of BRCA2 mutations in early-onset breast cancer may be due to a later age of onset in BRCA2 heterozygotes, rather than to a lower lifetime penetrance.

The probability of detecting a BRCA mutation in unselected series of ovarian cancer patients is approximately 4.6% for BRCA1 and 1.8% for BRCA2.

While BRCA mutations are infrequent in unselected breast and ovarian cancer patients, they are more often observed in individuals presenting to familial cancer clinics. In a series of reports describing various high-risk ascertainments around the world, the probability of detecting mutations in either gene ranged from 21-73% (reviewed in ref. 14).

These ascertainments are clearly not uniform and include families from differing ethnic backgrounds at higher and lower levels of risk. In the most striking families, such as those participating in the Breast Cancer Linkage Consortium effort to isolate BRCA1 and BRCA2, the probability that the predisposition is linked to BRCA1 or BRCA2 is up to 87%. Factors such as lower average age at onset of breast cancer or the occurrence of bilateral breast cancer, ovarian cancer or male breast cancer in a pedigree increase the likelihood of linkage to BRCA1 or BRCA2 (Table 11.1).

Unfortunately, current technology fails to detect mutations in a significant proportion of families that are attributable to BRCA1 or BRCA2 by traditional linkage analysis. This may be due in part to the presence of so-called regulatory mutations, or to the presence of large deletions/insertions. BRCA1 mutations have only been detected in approximately 64% of the strongly linked families that have undergone direct mutation testing. Similar data regarding sensitivity are not available for BRCA2.

Mark E. Robson
Breast conservation therapy for invasive breast cancer in Ashkenazi women with BRCA gene founder mutations. J Natl Cancer Inst 2003

References