Breast Cancer Research and Treatment

, Volume 149, Issue 1, pp 223–227 | Cite as

Incidence of BRCA1 and BRCA2 non-founder mutations in patients of Ashkenazi Jewish ancestry

  • Eric RosenthalEmail author
  • Kelsey Moyes
  • Christopher Arnell
  • Brent Evans
  • Richard J. Wenstrup


An estimated 1:40 individuals of Ashkenazi Jewish (AJ) ancestry carry one of three common founder mutations in BRCA1 or BRCA2, resulting in the inherited cancer condition, Hereditary Breast and Ovarian Cancer (HBOC) syndrome. Targeted testing for these three mutations (BRCA1 187delAG, BRCA1 5385insC, and BRCA2 6174delT) is therefore recommended for all AJ breast and ovarian cancer patients, regardless of age of diagnosis or family history. Comprehensive analysis of both genes is recommended for a subset of AJ patients in whom founder mutations are not identified, but estimates of the yield from comprehensive analysis in this population vary widely. We sought to determine the proportion of non-founder mutations as a percentage of all mutations in BRCA1 and BRCA2 among AJ patients to inform decisions about HBOC testing strategies in this population. We analyzed the genetic testing results for 37,952 AJ patients for whom clinical testing of BRCA1 and BRCA2 was performed at Myriad Genetic Laboratories from January 2006 through August 2013. Analysis was limited to AJ-only patients for whom the initial test order was either (1) comprehensive testing, or (2) founder mutation testing with instructions to automatically “reflex” to comprehensive analysis if negative. Cases were excluded if a separate follow-up order was placed to reflex to comprehensive analysis only after the founder mutation testing was reported out as negative. Among all BRCA1 and BRCA2 mutations detected in these groups, the percentage of non-founder mutations was 13 % (104/802) and 7.2 % (198/2,769). One-hundred and eighty-nine unique non-founder mutations were detected, 76 in BRCA1 and 113 in BRCA2. Non-founder mutations make up between 7.2 and 13.0 % of all BRCA1 and BRCA2 mutations in Ashkenazi Jews. A wide range of mutations are present, most of which are also seen in non-AJ individuals.


Hereditary Breast and Ovarian Cancer Ashkenazi Jewish Founder mutations BRCA1 BRCA2 



Ashkenazi Jewish


Hereditary Breast and Ovarian Cancer


Human Genome Variation Society


Large rearrangement


National Comprehensive Cancer Network



The authors acknowledge Heidi McCoy and Dmitry Pruss for their contributions to this project, and all of the Myriad staff who participate in the testing process and reporting of results to providers and patients. We would also like to thank Kirstin Roundy for her assistance in formatting and editing this manuscript.

Conflict of interest

The authors are full-time employees of Myriad Genetic Laboratories, Inc.


  1. 1.
    Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, Tang J, Li S, Zhang S, Shaw PA, Narod SA (2006) Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst 98(23):1694–1706. doi: 10.1093/jnci/djj465 CrossRefPubMedGoogle Scholar
  2. 2.
    Anglian Breast Cancer Study Group (2000) Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Br J Cancer 83(10):1301–1308. doi: 10.1054/bjoc.2000.1407 CrossRefPubMedCentralGoogle Scholar
  3. 3.
    Antoniou AC, Gayther SA, Stratton JF, Ponder BA, Easton DF (2000) Risk models for familial ovarian and breast cancer. Genet Epidemiol 18(2):173–190. doi: 10.1002/(SICI)1098-2272(200002)18:2<173:AID-GEPI6>3.0.CO;2-R CrossRefPubMedGoogle Scholar
  4. 4.
    Roa BB, Boyd AA, Volcik K, Richards CS (1996) Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 14(2):185–187. doi: 10.1038/ng1096-185 CrossRefPubMedGoogle Scholar
  5. 5.
    Hartge P, Struewing JP, Wacholder S, Brody LC, Tucker MA (1999) The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am J Hum Genet 64(4):963–970CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    King MC, Marks JH, Mandell JB, New York Breast Cancer Study Group (2003) Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302(5645):643–646. doi: 10.1126/science.1088759 CrossRefPubMedGoogle Scholar
  7. 7.
    Moslehi R, Chu W, Karlan B, Fishman D, Risch H, Fields A, Smotkin D, Ben-David Y, Rosenblatt J, Russo D, Schwartz P, Tung N, Warner E, Rosen B, Friedman J, Brunet JS, Narod SA (2000) BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am J Hum Genet 66(4):1259–1272. doi: 10.1086/302853 CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    National Comprehensive Cancer Network (2014) Genetic/familial high-risk assessment: breast and ovarian. NCCN Clinical Practice Guidelines in Oncology (1.2014)Google Scholar
  9. 9.
    Kauff ND, Perez-Segura P, Robson ME, Scheuer L, Siegel B, Schluger A, Rapaport B, Frank TS, Nafa K, Ellis NA, Parmigiani G, Offit K (2002) Incidence of non-founder BRCA1 and BRCA2 mutations in high risk Ashkenazi breast and ovarian cancer families. J Med Genet 39(8):611–614CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Frank TS, Deffenbaugh AM, Reid JE, Hulick M, Ward BE, Lingenfelter B, Gumpper KL, Scholl T, Tavtigian SV, Pruss DR, Critchfield GC (2002) Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 20(6):1480–1490CrossRefPubMedGoogle Scholar
  11. 11.
    Judkins T, Rosenthal E, Arnell C, Burbidge LA, Geary W, Barrus T, Schoenberger J, Trost J, Wenstrup RJ, Roa BB (2012) Clinical significance of large rearrangements in BRCA1 and BRCA2. Cancer 118(21):5210–5216. doi: 10.1002/cncr.27556 CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Stadler ZK, Saloustros E, Hansen NA, Schluger AE, Kauff ND, Offit K, Robson ME (2010) Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families. Breast Cancer Res Treat 123(2):581–585. doi: 10.1007/s10549-010-0818-y CrossRefPubMedGoogle Scholar
  13. 13.
    Beaudet AL, Tsui LC (1993) A suggested nomenclature for designating mutations. Hum Mutat 2(4):245–248. doi: 10.1002/humu.1380020402 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Eric Rosenthal
    • 1
    Email author
  • Kelsey Moyes
    • 1
  • Christopher Arnell
    • 1
  • Brent Evans
    • 1
  • Richard J. Wenstrup
    • 1
  1. 1.Myriad Genetic Laboratories, Inc.Salt Lake CityUSA

Personalised recommendations