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Updated: Jan 7, 2026
Identifying the Effects of BRCA1 Mutations on Homologous Recombination using Cells that Express Endogenous Wild-type BRCA1
Published on: February 17, 2011
The Risk of Breast Cancer According to Mutation Type and Position in Carriers of a Pathogenic Variant in BRCA1
Joanne Kotsopoulos1,2, Adriana I Apostol1,3, Kelly Metcalfe1,4
1Women's College Research Institute, University of Toronto, Toronto, ON M5S 1A1, Canada.
Background:
Carriers of a pathogenic variant (PV) in BRCA1 face a high risk of breast cancer. This study estimated the risk of developing breast cancer according to mutation type and location.
Methods:
BRCA1 carriers with no personal history of breast cancer or bilateral mastectomy were included. Detailed information on clinical and family history was collected by questionnaire. Survival analysis was used to estimate 15-year cumulative risk according to PV type and location.
Results:
A total of 3677 BRCA1 carriers were followed for a mean of 7.2 years (range 0.1-15.0 years); 481 incident breast cancers were documented. Overall, the 15-year cumulative incidence was 25%. Risk estimates varied by exon, ranging from 9% (exon 21) to 19% (exon 12) to 36% (exon 15); however, strata were small. Carriers of four founder mutations common in Eastern Europe (c.5263_5264insC, c.181T > G, c.66_67delAG and c.4034delA) experienced a lower-than-expected cancer risk (15.9-24.4%) compared to other PVs (28.8%) (p = 0.02).
Conclusions:
Although our data suggests some variability in penetrance based on specific BRCA1 PV, this was based on a large number of founder mutations. Breast cancer management strategies should continue to be based on comprehensive risk assessment.
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