We have analyzed 20 breast-ovarian cancer families, the majority of wh
ich show positive evidence of linkage to chromosome 17q12, for germ-li
ne mutations in the BRCA1 gene. BRCA1 mutations cosegregating with bre
ast and ovarian cancer susceptibility were identified in 16 families,
including 1 family with a case of male breast cancer. Nine of these mu
tations have not been reported previously. The majority of mutations w
ere found to generate a premature stop codon leading to the formation
of a truncated BRCA1 protein of 2%-88% of the expected normal length.
Two mutations altered the RING finger domain. Sequencing of genomic DN
A led to the identification of a mutation in the coding region of BRCA
1 in 12 families, and cDNA analysis revealed an abnormal or missing BR
CA1 transcript in 4 of the 8 remaining families. A total of eight muta
tions were associated with a reduced quantity of BRCA1 transcript. We
were unable to detect BRCA1 mutations in 4 of the 20 families, but onl
y 1 of these was clearly linked to BRCA1. Ir is expected that the majo
rity of clear examples of the breast-ovarian cancer syndrome will be a
ssociated with germ-line mutations in the coding region of BRCA1.