Three of Seven BRCA1 Mutations Definitively Linked to Cancer Development

Statistical evidence suggests that women with a mutation in this gene have a 40% to 90% risk of developing ovarian cancer and between 20% and 70% risk of developing breast cancer.

Investigators at Bellvitge Biomedical Research Institute (Barcelona, Spain) and the Catalan Institute of Oncology (Barcelona, Spain) combined computer structural analysis prediction tools with an in vitro transcription activation (TA) assay to functionally assess a set of seven missense variants of uncertain significance (VUS) labeled Q1409L, S1473P, E1586G, R1589H, Y1703S, W1718L and G1770V located in the C-terminal region of BRCA1.

They reported in the April 17, 2013, online edition of the journal PLoS One that the computer prediction programs gave discrepant results making their interpretation difficult. On the other hand, structural analysis of the three variants located in the BRCT domains (Y1703S, W1718L, and G1770V) revealed significant alterations of BRCT structure. The TA assay showed that variants Y1703S, W1718L, and G1770V dramatically compromised the transcriptional activity of BRCA1, while variants Q1409L, S1473P, E1586G, and R1589H behaved like wild-type BRCA1. Thus, three of the VUS had significant functional impact and may represent pathogenic BRCA1 variants while the remaining four did not have a functional impact.

"In the functional study we analyzed in vitro one of the key functions of BRCA1: regulation of transcription," said senior author Dr. Conxi Lázaro, coordinator of the molecular diagnostics units of the hereditary cancer program at the Catalan Institute of Oncology. "The analysis involves the generation of mutants of all variants in specific vectors to assess the transcriptional activity of the mutant compared to the control activity of the wild-type sequence of the BRCA1 gene. Now we know a lot of genetic alterations in BRCA1 that are clearly pathogenic alterations, neutral alterations, and sequence polymorphisms, but genetic diagnostic studies also identify changes in the DNA sequence, which we do not know its biological significance."

"To the individuals who carry the mutation we can offer a comprehensive clinical monitoring and the possibility of reproductive options, such as prenatal or preimplantation diagnosis," said Dr. Lazaro, "while members of the family who do not have the mutation can be considered as general population."

Related Links:
Bellvitge Biomedical Research Institute
Catalan Institute of Oncology