Prevalence of BRCA mutations and founder effect in high-risk Hispanic families

Approximately 12% of the U.S. population is Hispanic, with the majority residing in urban centers such as Los Angeles. The prevalence of BRCA mutations among high-risk Hispanic families is unknown.

One hundred and ten unrelated probands of Hispanic origin, with a personal or family history of breast and/or ovarian cancer, presented for genetic cancer risk assessment, were enrolled in an Institutional Review Board-approved registry and underwent BRCA testing. Haplotype analyses were done if BRCA mutations were observed in two or more unrelated probands.

Mean age at diagnosis was 37 years (range = 23-59) for the 89 (81%) probands with invasive breast cancer. Overall, 34 (30.9%) had deleterious mutations (25 in BRCA1, 9 in BRCA2), 25 (22.7%) had one or more unclassified variants, and 51 (46.4%) had negative results. The mean pretest mutation probability using the Couch model, Myriad model, and BRCAPro was 19.6% (range = 4-77%). The combined average mutation probability was 32.8% for carriers, 15.5% for noncarriers, and 12.9% for variant carriers (P < 0.0001). The most common deleterious mutation was 185delAG (4 of 34, 11.8%). The Hispanic 185delAG carrier families share the same haplotype from D17s1320 through BRCA1, as do two reference Ashkenazi Jewish families. Haplotype analyses of additional recurrent BRCA1 mutations [IVS5+1G>A (n=2),S955X (n = 3), R1443X (n = 3), and 2552delC (n = 2)] also suggest founder effects, with four of six mutations seen almost exclusively in families with Latin American/Caribbean or Spanish ancestry.

This is the largest study to date of high-risk Hispanic families in the United States. Six recurrent mutations accounted for 47% (16 of 34) of the deleterious mutations in this cohort. The BRCA1185delAG mutation was prevalent (3.6%) in this clinic-based cohort of predominantly Mexican descent, and shared the Ashkenazi Jewish founder haplotype.