Nature Genetics
14, 188 - 190 (1996)
doi:10.1038/ng1096-188
The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%Carole Oddoux1, Jeffery P. Struewing2, C. Mark Clayton1, Susan Neuhausen3, Lawrence C. Brody4, Michael Kaback5, Bruce Haas6, Larry Norton7, Patrick Borgen8, Suresh Jhanwar6, David Goldgar9, Harry Ostrer1, 10
& Kenneth Offit6
1Human Genetics Program, Department of Pediatrics, New York University Medical Center, New York, New York 10016, USA
2Genetic Epidemiology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
3Genetic Epidemiology Group, Department of Medical Informatics, University of Utah School of Medicine, Salt Lake City, Utah 84108, USA
4Laboratory of Gene Transfer, National Center for Human Genome Research, National Institutes of Health, Bethesda, Maryland 20892, USA
5Departmentof Pediatrics and Reproductive Medicine, University of California, San Diego, San Diego, California 92123, USA
6Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
7Breast Cancer Medicine Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
8Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021
9Unit of Genetic Epidemiology, International Agency for Research on Cancer, Lyon, Cedex 08, France
10e-mail: ostreh01@mcrcr6.med.nyu.edu Certain germline mutations in either BRCA1 or BRCA2 confer a lifetime risk of developing breast cancer that may approach 90% 1−3. The BRCA1 185delAG mutation was found in 20% and the BRCA2 6174delT mutation in 8% of Ashkenazi Jewish women with early-onset breast cancer4−6. The 185delAG mutation was observed in 0.9% of 858 Ashkenazi Jews unselected for a personal or family history of cancer7. Assuming comparable age-specific penetrances, a carrier frequency of 0.3% was estimated for the 6174delT BRCA2 mutation6. To test this hypothesis, we performed a population survey of 1,255 Jewish individuals. In two independent groups, a prevalence of approximately 1 % (C.I. 0.6−1.5) was observed for the 6174delT mutation. The relative risk of developing breast cancer by age 42 was estimated to be 9.3 (C.I. 2.5−22.5) for6174delT, compared to 31 (C.I. 11−77) for 185delAG. Analysis of 107 Ashkenazi Jewish women with breast cancer and a family history of breast or ovarian cancer confirmed a four-fold greater prevalence for the BRCA1 185delAG mutation compared to the BRCA2 6174delT mutation. Our findings suggest a difference in cumulative lifetime penetrance for the two mutations. Genetic counseling for the one in 50 Ashkenazi Jewish individuals harbouring specific germline mutations in BRCA1 or BRCA2 must be tailored to reflect the different risks associated with the two mutations.
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