Clinical Characteristics of Individuals With Germline Mutations in <i>BRCA1</i> and <i>BRCA2</i>: Analysis of 10,000 Individuals

TLDR

The study aims to identify which personal and family history features best predict BRCA1/BRCA2 mutation status in clinically tested individuals. The authors analyzed 10,000 consecutive BRCA1/BRCA2 gene tests—full sequencing in 7,461 cases and targeted Ashkenazi founder mutation screening in 2,539 cases—linking results to personal/family history, ancestry, breast cancer type, and sex. In the cohort, 17.2% of 10,000 individuals carried BRCA1/BRCA2 mutations, including 20% of breast‑cancer women and 34% of ovarian‑cancer women, with prevalence correlated to specific personal and family history features, ancestry, and cancer type, demonstrating that these characteristics can predict mutation likelihood.

Abstract

PURPOSE: To assess the characteristics that correlate best with the presence of mutations in BRCA1 and BRCA2 in individuals tested in a clinical setting. PATIENTS AND METHODS: The results of 10,000 consecutive gene sequence analyses performed to identify mutations anywhere in the BRCA1 and BRCA2 genes (7,461 analyses) or for three specific Ashkenazi Jewish founder mutations (2,539 analyses) were correlated with personal and family history of cancer, ancestry, invasive versus noninvasive breast neoplasia, and sex. RESULTS: Mutations were identified in 1,720 (17.2%) of the 10,000 individuals tested, including 968 (20%) of 4,843 women with breast cancer and 281 (34%) of 824 with ovarian cancer, and the prevalence of mutations was correlated with specific features of the personal and family histories of the individuals tested. Mutations were as prevalent in high-risk women of African (25 [19%] of 133) and other non-Ashkenazi ancestries as those of European ancestry (712 [16%] of 4379) and were significantly less prevalent in women diagnosed before 50 years of age with ductal carcinoma in situ than with invasive breast cancer (13% v 24%, P = .0007). Of the 74 mutations identified in individuals of Ashkenazi ancestry through full sequence analysis of both BRCA1 and BRCA2, 16 (21.6%) were nonfounder mutations, including seven in BRCA1 and nine in BRCA2. Twenty-one (28%) of 76 men with breast cancer carried mutations, of which more than one third occurred in BRCA1. CONCLUSION: Specific features of personal and family history can be used to assess the likelihood of identifying a mutation in BRCA1 or BRCA2 in individuals tested in a clinical setting.