Last December, the race to unearth the second hereditary breast and ovarian cancer gene, BRCA2, was concluded. Michael Stratton and colleagues reported that they had identified part of the massive BRCA2 gene on chromosome 13 and identified six mutations in families with breast and ovarian cancer, including some cases of male breast cancer (Nature 378, 789-781; 1995). Not to be outdone, however, scientists at Myriad Genetics, who had isolated BRCA1 in 1994, rushed to submit a patent application for BRCA2 coinciding with the publication of the Nature paper. In remarkably little time, the group and its collaborators had managed — with the help of the 900 kilobases of publicly available genomic DNA sequence — to assemble the complete gene sequence (GenBank accession number U43746). The fruits of that endeavour are presented by Tavtigian et al. on page 333, together with the first results of a mutational analysis for the entire coding region.

If BRCA1 was a large gene, then BRCA2 is gargantuan. The gene encodes a protein of 3,418 amino acids (Stratton et al. presented about 68% of the coding sequence in their paper). And while BRCA2 certainly contains some general similarities to BRCA1, Tavtigian et al. report that BRCA2 shows no significant homologies with BRCA1 or anything else in the database for that matter. However, results presented on page 298 of this issue by the teams of Jeffrey Holt and Roy Jensen at Vanderbilt University, and Mary-Claire King at the University of Washington in Seattle, suggest that there may be a significant motif in both BRCA1 and BRCA2. The sequence in question is the granin consensus site (see News & Views on page 223), which is located in the middle of BRCA1 but in the more orthodox C-terminal region of BRCA2. It should be stressed that no functional studies have yet been performed on BRCA2, and indeed the evidence for BRCA1 acting as a granin is largely circumstantial at this stage.

The Myriad group has also uncovered nine separate mutations in different families, out of a total of 18 tested which were thought likely to be attributable to a flaw in BRCA2. The results are both good and bad from the perspective of genetic testing. The bad news is that each of the 15 mutations published so far are distinct, apparently thwarting those who had hoped that genetic predisposition at this locus might be confined to a small number of defects. However, virtually all of the mutations witnessed so far are nonsense or frameshift mutations, which might simplify the task of genetic testing. Who will reap the rewards from such tests is another question entirely. Two rival patent applications have been submitted in the United Kingdom and United States. Each group obviously feels it has a case: the European group was the first to publish evidence that BRCA2 had been cloned, by virtue of documenting a handful of mutations in affected families. By contrast, the Myriad team points to having been the first to compile the full-length sequence of the gene. Even as the process of evaluating these claims begins, there is the possibility that the two teams will reach some form of cross-licensing agreement.