The germline mutational landscape of BRCA1 and BRCA2 in Brazil

Abstract

The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.

Figure 1

Geographical distribution of HBOC patients with pathogenic and likely pathogenic BRCA1 and BRCA2 variants in Brazil (N = 649). Legends represent the Brazilian States of Amazonas (AM), Pará (PA), Ceará (CE), Rio Grande do Norte (RN), Bahia (BA), Minas Gerais (MG), Espírito Santo (ES), Rio de Janeiro (RJ), São Paulo (SP), Santa Catarina (SC) and Rio Grande do Sul (RS) and the numbers indicate the number of cases reported from each State. The five Brazilian regions are depicted in different colors and the number between parentheses indicate the approximated population of each region.

Figure 2

Frequency of each type of variation and molecular consequence among reported BRCA1 and BRCA2 mutations. SNV, single nucleotide variants; LGR, large genomic rearrangements.

Figure 3

Circos plot showing the distribution of all reported BRCA1 mutations. Point mutations and small deletions and insertions are shown around in the outermost ring, which represents the BRCA1 exons. The number between brackets correspond to the number of mutation carriers. Each reported LGR is represented by dashed blocks in the three intermediate rings, while the innermost ring represent the BRCA1 domains.

Figure 4

Circos plot showing the distribution of all reported BRCA2 mutations. Point mutations and small deletions and insertions are shown around in the outermost ring, which represents the BRCA2 exons. The number between brackets correspond to the number of mutation carriers. Each reported LGR is represented by dashed blocks in the intermediate ring, while the innermost ring represent the BRCA2 domains.