Two genes, called BRCA-1 and BRCA-2, have been identified that appear
to be responsible for the majority of familial breast cancer syndromes
. These genes now play a prominent role in the practice of the surgeon
treating breast cancer. Additional genes, PTEN (Cowden disease), MSH1
or MLH2 (HNPCC), and p53 (Li-Fraumeni syndrome) are responsible for o
ther breast cancer syndromes but have not yet entered the clinical are
na on a large scale. The risk of breast and ovaran cancer by age 70 in
a BRCA-1 mutation carrier is estimated at 55-75% and 16-26%, respecti
vely, overall, and as high as 87% and 44% in those with a strong famil
y history. The cancer risks associated with BRCA-2 mutations appear to
be somewhat lower than those of BRCA-1. BRCA mutations show a strong
founder effect. This is best recognized in the Ashkenazi Jewish commun
ity, in which the incidence of one of three characteristic mutations i
s about 2%. In other ethnic groups the pattern of mutations is differe
nt, with over 100 distinct mutations throughout the genes having been
described. Most mutations so far have been frame-shift or mis-sense mu
tations, although large deletions have also been described. Thus, in m
ost situations, assessment of the whole coding sequence is required to
confirm or exclude a mutation. Guidelines to suggest who is likely to
be a mutation carrier are being clarified, but the appropriate manage
ment of someone who tests positive remains difficult. Prophylactic mas
tectomy and oophorectomy are likely to offer substantial gains in life
expectancy to mutation carriers, especially for young women with a st
rong family history. Unfortunately, there are no currently available s
trategies to eliminate the risk of breast or ovarian cancer. The psych
ological impact of testing also remains poorly understood, and the dan
ger of various forms of discrimination remain. These factors must be c
learly understood by all parties prior to testing. The process of a dy
namic, interactive informed consent-much more than a simple printed do
cument-and also counseling are central to the testing process. (C) 199
8 Wiley-Liss, Inc.