Frequency and Carrier Risk Associated with Common BRCA1 and BRCA2 Mutations in Ashkenazi Jewish Breast Cancer Patients

Abstract

Based on breast cancer families with multiple and/or early-onset cases, estimates of the lifetime risk of breast cancer in carriers of BRCA1 or BRCA2 mutations may be as high as 85%. The risk for individuals not selected for family history or other risk factors is uncertain. We determined the frequency of the common BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) mutations in a series of 268 anonymous Ashkenazi Jewish women with breast cancer, regardless of family history or age at onset. DNA was analyzed for the three mutations by allele-specific oligonucleotide hybridization. Eight patients (3.0%, 95% confidence interval [CI] 1.5%-5.8%) were heterozygous for the 185delAG mutation, two (0.75%, 95% CI 0.20-2.7) for the 5382insC mutation, and eight (3.0%, 95% CI 1.5-5.8) for the 6174delT mutation. The lifetime risk for breast cancer in Ashkenazi Jewish carriers of the BRCA1 185delAG or BRCA2 6174delT mutations was calculated to be 36%, approximately three times the overall risk for the general population (relative risk 2.9, 95% CI 1.5-5.8). For the 5382insC mutation, because of the low number of carriers found, further studies are necessary. The results differ markedly from previous estimates based on high-risk breast cancer families and are consistent with lower estimates derived from a recent population-based study in the Baltimore area. Thus, presymptomatic screening and counseling for these common mutations in Ashkenazi Jewish women not selected for family history of breast cancer should be reconsidered until the risk associated with these mutations is firmly established, especially since early diagnostic and preventive-treatment modalities are limited.

A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families

“…Studies of breast cancer patients have indicated that it may be difficult to define mutation screening criteria among women with minimal or no family history (Malone et al, 1998). Furthermore, the carrier risks associated with the mutations may be highly variable, and population-based risk estimates have indicated much lower cancer risks than those obtained from multiplecase families and, therefore, lower predictive value of cancer for a positive mutation test result (Struewing et al, 1997;Fodor et al, 1998;Thorlacius et al, 1998;Warner et al, 1999). Accordingly, genetic screening would be of greatest benefit in families with high cancer risk, i.e.…”

“…Accordingly, genetic screening would be of greatest benefit in families with high cancer risk, i.e. strong family history (Fodor et al, 1998), and a high probability of harbouring a BRCA1 or BRCA2 mutation. For this study, we chose families with a defined family history, and developed a model by which likelihood of carrying a BRCA1 or BRCA2 mutation can be estimated for each family separately.…”

Body weight and risk of breast cancer in BRCA1/2 mutation carriers

“…The estimated lifetime risk of developing breast cancer for BRCA1/2 mutation carriers (carriers) varies between 30 and 80% [1][2][3][4][5][6]. Reasons for variation may include different mutations in the same gene (allelic variation) [5,[7][8][9], the effect of modifying genes [10][11][12], and non-genetic modifiers [13].…”

The frequency of the predominant Jewish mutations in BRCA1 and BRCA2 in unselected Ashkenazi colorectal cancer patients

“…Furthermore, these mutations occur at a rate of about 2.5% among the general Jewish Ashkenazi population (Struewing et al, 1995(Struewing et al, , 1997Roa et al, 1996;Fodor et al, 1998).…”