CONTEXT: An autosomal dominant pattern of hereditary breast cancer may be masked 
by small family size or transmission through males given sex-limited expression.
OBJECTIVE: To determine if BRCA gene mutations are more prevalent among single 
cases of early onset breast cancer in families with limited vs adequate family 
structure than would be predicted by currently available probability models.
DESIGN, SETTING, AND PARTICIPANTS: A total of 1543 women seen at US high-risk 
clinics for genetic cancer risk assessment and BRCA gene testing were enrolled 
in a prospective registry study between April 1997 and February 2007. Three 
hundred six of these women had breast cancer before age 50 years and no first- 
or second-degree relatives with breast or ovarian cancers.
MAIN OUTCOME MEASURE: The main outcome measure was whether family structure, 
assessed from multigenerational pedigrees, predicts BRCA gene mutation status. 
Limited family structure was defined as fewer than 2 first- or second-degree 
female relatives surviving beyond age 45 years in either lineage. Family 
structure effect and mutation probability by the Couch, Myriad, and BRCAPRO 
models were assessed with stepwise multiple logistic regression. Model 
sensitivity and specificity were determined and receiver operating 
characteristic curves were generated.
RESULTS: Family structure was limited in 153 cases (50%). BRCA gene mutations 
were detected in 13.7% of participants with limited vs 5.2% with adequate family 
structure. Family structure was a significant predictor of mutation status (odds 
ratio, 2.8; 95% confidence interval, 1.19-6.73; P = .02). Although none of the 
models performed well, receiver operating characteristic analysis indicated that 
modification of BRCAPRO output by a corrective probability index accounting for 
family structure was the most accurate BRCA gene mutation status predictor (area 
under the curve, 0.72; 95% confidence interval, 0.63-0.81; P<.001) for single 
cases of breast cancer.
CONCLUSIONS: Family structure can affect the accuracy of mutation probability 
models. Genetic testing guidelines may need to be more inclusive for single 
cases of breast cancer when the family structure is limited and probability 
models need to be recreated using limited family history as an actual variable.