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Incidence of non-founder BRCA1 and BRCA2 mutations in high risk Ashkenazi breast and ovarian cancer families
  1. N D Kauff1,
  2. P Perez-Segura2,
  3. M E Robson1,
  4. L Scheuer1,
  5. B Siegel1,
  6. A Schluger1,
  7. B Rapaport1,
  8. T S Frank3,
  9. K Nafa1,
  10. N A Ellis1,
  11. G Parmigiani4,
  12. K Offit1
  1. 1Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
  2. 2Department of Medical Oncology, San Carlos University Hospital, Madrid, Spain
  3. 3Myriad Genetics Laboratories, Salt Lake City, UT, USA
  4. 4Departments of Oncology and Biostatistics, Johns Hopkins University, Baltimore, MD, USA
  1. Correspondence to:
 Dr N D Kauff, Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 192, New York, NY 10021, USA;
 kauffn{at}mskcc.org

https://doi.org/10.1136/jmg.39.8.611

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    Inherited predisposition to cancer is a major contributor to the breast and ovarian cancer burden among people of Ashkenazi ancestry. Approximately 2.5% of all people of Ashkenazi Jewish descent carry one of three ancient (founder) mutations in BRCA1 or BRCA2 (185delAG or 5382insC in BRCA1 and 6174delT in BRCA2).1–3 In a recent population based study, 29% of Jewish women with ovarian cancer were shown to carry one of these three founder mutations.4 In a series of 220 high risk Ashkenazi breast cancer families, a founder BRCA mutation was detected in 44%. If ovarian cancer was present in the kindred, 73% of families segregated a founder BRCA mutation.5

    Despite the high proportion of hereditary breast and ovarian cancer attributed to founder mutations of BRCA1 or BRCA2 in this population, some Ashkenazi families with histories highly suggestive of an inherited cancer predisposition have been shown to segregate other (non-founder) mutations of BRCA16 or BRCA2.7 Counselling of families considering full sequence BRCA genotyping is complicated by the limited information available regarding the incidence of these non-founder mutations in the Ashkenazi population.

    We present a series of Ashkenazi Jewish kindreds at hereditary risk for breast and ovarian cancer who do not segregate one of the three Ashkenazi founder mutations and who have undergone full sequencing of the coding regions and flanking intronic regions of BRCA1 and BRCA2. Using the BRCAPRO algorithm, we have estimated whether the prevalence of non-founder BRCA1 and BRCA2 mutations in a genetic isolate (Ashkenazim) is consistent with the background rate in an admixed population, or if selective or other effects have led to a non-founder mutation rate lower than would be expected.

    METHODS

    Records of all patients seen by the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center (MSKCC) from 1.6.95 to …

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