Screening for 185delAG in the Ashkenazim.

A study was initiated to assess interest, educational effectiveness, and implications of genetic testing for the common BRCA1 mutation, 185delAG, in the Ashkenazim. Of 333 individuals who attended group sessions, 309 (92%) participated in the study. Participants were categorized as having negative family history (67%), positive family history (defined, by a relaxed criterion, as one first-degree relative or two second-degree relatives with breast [premenopausal] or ovarian cancer) (22%), positive personal history (7%), and both positive personal history and positive family history (4%). Group education was effective, as shown by the improvement in participant scores from pre- to posteducation tests. For the 289 individuals (94%) who requested testing, the major reasons included concern for their own risk, concern for the risk of their children, and desire to learn about surveillance options. The most common reason given by participants who declined testing was concern about health insurance. Six participants found to be heterozygous for the 185delAG mutation received results and were offered genetic counseling. Participants had consented for additional testing without receiving results and were screened for the 6174delT mutation in BRCA2, and seven were found to be positive. All identified carriers reported at least one first- or second-degree relative with a history of breast or ovarian cancer, although they did not all meet our study criteria for positive family history. Given these outcomes, we conclude that screening for breast and ovarian cancer susceptibility is most appropriate for individuals with a positive personal or positive family cancer history. We propose a guideline for future studies designed to identify individuals who may benefit from genetic testing for inherited breast and ovarian cancer.

Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2.

BRCA1 and BRCA2 are the two major identified causes of inherited breast cancer, with mutations in either gene conferring up to 80-90% lifetime risk of breast cancer in carrier females. Mutations in BRCA1 account for approximately 45% of familial breast cancer and 90% of inherited breast/ovarian cancer, whereas mutations in BRCA2 account for a comparable percentage of inherited breast cancer cases. Over 85 distinct BRCA1 mutations and a growing list of BRCA2 mutations have been identified, with the majority resulting in protein truncation. A specific BRCA1 mutation, 185delAG, has a reported increased carrier frequency of approximately 0.9% in the Ashkenazi Jewish population, but is also found in rare non-Jewish patients with a different haplotype. The 6174delT mutation in BRCA2 was recently identified as a frequent mutation in 8 out of 107 Ashkenazi Jewish women diagnosed with breast cancer by age 50 (ref. 8), as well as in three Ashkenazi male breast cancer patients. We have conducted a large-scale population study to investigate the prevalence of specific BRCA1 and BRCA2 mutations in Ashkenazi Jewish individuals who were unselected for breast cancer. BRCA1 mutation screening on approximately 3,000 Ashkenazi Jewish samples determined a carrier frequency of 1.09% for the 185delAG mutation and 0.13% for the 5382insC mutation. BRCA2 analysis on 3,085 individuals from the same population showed a carrier frequency of 1.52% for the 6174delT mutation. This expanded population-based study confirms that the BRCA1 185delAG mutation and the BRCA2 6174delT mutation constitute the two most frequent mutation alleles predisposing to hereditary breast cancer among the Ashkenazim, and suggests a relatively lower penetrance for the 6174delT mutation in BRCA2.