<i>BRCA1</i> and <i>BRCA2</i> mutations in women of different ethnicities undergoing testing for hereditary breast‐ovarian cancer

TLDR

In women at increased risk for breast and ovarian cancer, identifying BRCA1 and BRCA2 mutations informs screening and prevention, yet prevalence estimates vary across non‑white populations, creating uncertainty about testing utility. The study aimed to determine the prevalence of deleterious BRCA1 and BRCA2 mutations among a large, ethnically diverse cohort of women referred for genetic testing. A cross‑sectional analysis of 46,276 women who underwent full‑sequence DNA analysis of BRCA1 and BRCA2 from 1996 to 2006 was performed. Deleterious mutations were found in 12.5% of participants, with higher rates in African (15.6%) and Latin American (14.8%) women compared to Western Europeans (12.1%); non‑European ethnicity was also linked to more variants of uncertain significance, though reclassification reduced reporting, underscoring the importance of BRCA1/2 testing across all high‑risk women.

Abstract

In women at increased risk for breast and ovarian cancer, the identification of a mutation in breast cancer gene 1 (BRCA1) and BRCA2 has important implications for screening and prevention counseling. Uncertainty regarding the role of BRCA1 and BRCA2 testing in high-risk women from diverse ancestral backgrounds exists because of variability in prevalence estimates of deleterious (disease-associated) mutations in non-white populations. In this study, the authors examined the prevalence of BRCA1 and BRCA2 mutations in an ethnically diverse group of women who were referred for genetic testing.In this cross-sectional analysis, the prevalence of BRCA1 and BRCA2 mutations was assessed in a group of non-Ashkenazi Jewish women who underwent genetic testing.From 1996 to 2006, 46,276 women who met study criteria underwent DNA full-sequence analysis of the BRCA1 and BRCA2 genes. Deleterious mutations were identified in 12.5% of women, and recurrent deleterious mutations (prevalence >2%) were identified in all ancestral groups. Women of non-European descent were younger (mean age, 45.9 years; standard deviation [SD], 11.6 years) than European women (mean age, 50 years; SD, 11.9 years; P < .001). Women of African (15.6%; odds ratio [OR], 1.3 [95% confidence interval (95% CI), 1.1-1.5]) and Latin American (14.8%; OR, 1.2 [95% CI, 1.1-1.4]) ancestries had a significantly higher prevalence of deleterious BRCA1 and BRCA2 mutations compared with women of Western European ancestry (12.1%), primarily because of an increased prevalence of BRCA1 mutations in those 2 groups. Non-European ethnicity was associated strongly with having a variant of uncertain significance; however, reclassification decreased variant reporting (from 12.8%-->5.9%), and women of African ancestry experienced the largest decline (58%).Mutation prevalence was found to be high among women who were referred for clinical BRCA1 and BRCA2 testing, and the risk was similar across diverse ethnicities. BRCA1 and BRCA2 testing is integral to cancer risk assessment in all high-risk women.