A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene: implications for presymptomatic testing and screening

Many of the mutations identified in the BRCA1 gene may result in a truncated protein product and three BRCA1 gene mutations may occur more often than others. Women who have a mutation in the BRCA1 gene are predisposed to breast and ovarian cancer. Researchers in nine laboratories in North America and the United Kingdom took blood or tumor samples from 1,086 women with breast or ovarian cancer to test the patients' DNA for BRCA1 gene mutations. DNA samples from 63 women contained a total of 38 unique mutations. Of these, most were frameshift mutations that are caused by the insertion or deletion of at least one nucleotide. This type of mutation can affect protein translation most often through premature truncation of the protein product. The mutations were distributed throughout many regions of the BRCA1 gene. Three common BRCA1 mutations accounted for 32% of the mutations identified in the DNA from 63 families.
Objectives. - To report the initial experience of an international group of investigator's in identifying mutations in the BRCA1 breast and ovarian cancer susceptibility gene, to assess the spectrum of such mutations in samples from patients with different family histories of cancer, and to determine the frequency of recurrent mutations. Design. - Nine laboratories in North America and the United Kingdom tested for BRCA1 mutations in DNA samples obtained from a total of 372 unrelated patients with breast or ovarian cancer largely chosen from high-risk families. Three of these laboratories also analyzed a total of 714 additional samples from breast or ovarian cancer cases, including 557 unselected for family history, for two specific mutations that had been found to recur in familial samples. Participants. - A total of 1086 women with either breast or ovarian cancer. Main Outcome Measure. - The detection of sequence variation in patients' DNA samples that is not found in sets of control samples. Results. - BRCA1 mutations have now been identified in a total of 80 patient samples. Thirty-eight distinct mutations were found among 63 mutations identified through a complete screen of the BRCA1 gene. Three specific mutations appeared relatively common, occurring eight, seven, and five times, respectively. When specific tests for the two most common mutations were performed in larger sets of samples, they were found in 17 additional patients. Mutations predicted to result in a truncated protein accounted for 86% of the mutations detected by complete screening. Conclusions. - The high frequency of protein-terminating mutations and the observation of many recurrent mutations found in a diverse set of samples could lead to a relatively simple diagnostic test for BRCA1 mutations. More data must be accumulated to address specifically the sensitivity and specificity of such a diagnostic testing procedure and to better estimate the age-specific risk for breast and ovarian cancer associated with such mutations.