A MISSENSE MUTATION IN THE BRCA2 GENE IN 3 SIBLINGS WITH OVARIAN-CANCER

Inherited susceptibility to ovarian cancer has been associated with ge rmline defects at several loci. The major known ovarian cancer suscept ibility gene is BRCA1 on chromosome 17q, which confers a risk of appro ximately 60% by the age of 70 years. Truncating mutations in BRCA2 on chromosome 13q also predispose to ovarian cancer, although they confer a lower risk than mutations in BRCA1. We have studied the molecular b asis of ovarian cancer predisposition in a Finnish family with three a ffected sisters. Analysis of polymorphic markers provided evidence aga inst linkage to BRCA1, but the sibship was consistent with linkage to BRCA2. Conformation-sensitive gel electrophoresis was used to screen t he entire coding sequence of BRCA2. A G to A transition at nucleotide 8702 was observed, which is predicted to convert glycine 2901 to aspar tate in the encoded protein. This sequence variant was not detected in 220 cancer-free Finnish control individuals, or in several hundred ca ncer families of many nationalities previously screened for BRCA2 muta tions. Taken together with the fact that this amino acid residue and t he surrounding region of BRCA2 is identical in mouse and chicken, the data suggest that this alteration is a disease-causing BRCA2 missense mutation. Previously published data indicate that the risks of breast and ovarian cancer conferred by BRCA2-truncating mutations Varies with the position of the mutation in the gene. The missense mutation repor ted here suggests that the BRCA2 domain including and surrounding glyc ine 2901 may be more important in preventing neoplastic transformation in ovarian epithelium than in breast epithelium.