A novel BRCA2 gene mutation, 4081 insA, in a Finnish breast/ovarian cancer family associated with favourable clinical course

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Annually more than 3000 new breast and 400 ovarian cancer cases are diagnosed in Finland. It is estimated that inherited predisposing genes will cause 150-320 cases of breast and 20-40 cases of ovarian cancer each year. In Finland 18 different BRCA1/2 mutations have been found. Eleven of these mutations are recurrent (including four founder mutations unique to Finland) and one of 18 is unique to one family (4081insA). We have studied 38 Eastern Finnish breast/ovarian cancer families for BRCA1 and BRCA2 germline mutations. The 4081insA mutation was detected in PTT analysis and it was confirmed by heteroduplex, sequencing and haplotype analysis. The insertion of an adenine causes frameshift, which leads to a translation terminating signal and protein truncation at codon 1288. The 4081insA mutation is in the BRCA2 gene ovarian cancer cluster region (OCCR) in exon 11. We screened a family of the index patient, her three brothers and four sisters. Mutation was found in three sisters and one brother, in addition to the index patient and one of her three sons. The 4081insA mutation is rare and has a high penetrance; four of six mutation carriers in the family are affected with breast (two cases) or ovarian cancer (two cases). There were no other cancer cases in the family. Two mutation carriers, both males, at the age of 76 and 59 years, are so far apparently healthy with no symptoms. The four sisters each had an advanced type of breast or ovarian cancer with a poor prognosis. However, they all had a good response to treatment and after 9 to 19 years follow-up time no recurrence has been seen and all are alive and well. Although the mutation is highly penetrant, the breast and ovarian cancer patients carrying it, in this family, seem to have an exceptionally good clinical course.