Incidence of non-founder BRCA1 and BRCA2 mutations in high risk Ashkenazi breast and ovarian cancer families.

Inherited predisposition to cancer is a major contributor to the breast and ovarian cancer burden among people of Ashkenazi ancestry. Approximately 2.5% of all people of Ashkenazi Jewish descent carry one of three ancient (founder) mutations in BRCA1 or BRCA2 (185delAG or 5382insC in BRCA1 and 6174delT in BRCA2). In a recent population based study, 29% of Jewish women with ovarian cancer were shown to carry one of these three founder mutations. In a series of 220 high risk Ashkenazi breast cancer families, a founder BRCA mutation was detected in 44%. If ovarian cancer was present in the kindred, 73% of families segregated a founder BRCA mutation. Despite the high proportion of hereditary breast and ovarian cancer attributed to founder mutations of BRCA1 or BRCA2 in this population, some Ashkenazi families with histories highly suggestive of an inherited cancer predisposition have been shown to segregate other (non-founder) mutations of BRCA1 or BRCA2. Counselling of families considering full sequence BRCA genotyping is complicated by the limited information available regarding the incidence of these non-founder mutations in the Ashkenazi population. We present a series of Ashkenazi Jewish kindreds at hereditary risk for breast and ovarian cancer who do not segregate one of the three Ashkenazi founder mutations and who have undergone full sequencing of the coding regions and flanking intronic regions of BRCA1 and BRCA2. Using the BRCAPRO algorithm, we have estimated whether the prevalence of nonfounder BRCA1 and BRCA2 mutations in a genetic isolate (Ashkenazim) is consistent with the background rate in an admixed population, or if selective or other effects have led to a non-founder mutation rate lower than would be expected. METHODS Records of all patients seen by the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center (MSKCC) from 1.6.95 to 30.6.01, who identified themselves as being of Ashkenazi Jewish descent, and who consented to participate in an ongoing study evaluating the clinical significance of germline BRCA mutations, were reviewed. Seventy patients with a personal history of breast or ovarian cancer who underwent full sequence evaluation of BRCA1 and BRCA2 after testing negative for the three Ashkenazi founder mutations were identified. Demographic information for these patients is summarised in table 1. Founder mutation testing was performed in the Diagnostic Molecular Genetics Laboratory at MSKCC using previously published methods. In some cases, samples were split and were genotyped a second time at the University of Washington as part of an ongoing cohort study. Sequencing of the coding regions and flanking intronic regions was carried out by Myriad Genetics Laboratories as previously described. All deleterious mutations were confirmed by single amplicon DNA sequencing in the Diagnostic Molecular Genetics Laboratory at MSKCC. A three generation pedigree for each kindred was entered into the BRCAPRO model using CancerGene interface (Version 3.3, University of Texas Southwestern). BRCAPRO is a predictive model using pedigree information of first and second degree relatives and published prevalence 16 and penetrance 18 estimates of BRCA1 and BRCA2 for both Ashkenazi and non-Ashkenazi populations to determine the probability of a deleterious BRCA mutation in a person. The model incorporates statistical assumptions for autosomal