Fanconi anemia (FA) is a rare autosomal recessive disease characterized by a 
greatly increased risk of cancer among those diagnosed with the syndrome. The 
question as to whether FA heterozygotes are at increased risk for cancer is of 
great importance to those at risk for being a carrier. To address this question, 
we formed a cohort of grandparents of probands identified through the 
International Fanconi Anemia Registry. We obtained informed consent, a short 
questionnaire, and either blood or buccal swab DNA. After diagnosis of the 
proband was confirmed and complementation studies or DNA sequencing on the 
proband were completed, mutation analyses of the putative carriers and 
noncarriers was carried out. Standardized incidence ratios (SIR) were calculated 
to compare the observed cancer incidence of the grandparents and other relatives 
with the expected rates of cancer, using the Surveillance, Epidemiology, and End 
Results registries and the Connecticut Cancer registry. In the 944 study 
subjects who participated (784 grandparents and 160 other relatives), there was 
no suggestion of an increase in overall cancer incidence. On the other hand, a 
significantly higher rate of breast cancer than expected was observed among 
carrier grandmothers [SIR, 1.7; 95% confidence interval (95% CI), 1.1-2.7]. 
Among the grandmothers, those who were carriers of FANCC mutations were found to 
be at highest risk (SIR, 2.4; 95% CI, 1.1-5.2). Overall, there was no increased 
risk for cancer among FA heterozygotes in this study of Fanconi relatives, 
although there is some evidence that FANCC mutations are possibly breast cancer 
susceptibility alleles.