Breast Cancer Research and Treatment

, Volume 167, Issue 3, pp 697–702 | Cite as

The yield of targeted genotyping for the recurring mutations in BRCA1/2 in Israel

  • Rinat Bernstein-Molho
  • Yael Laitman
  • Hagit Schayek
  • Orit Reish
  • Shira Lotan
  • Sara Haim
  • Jamal Zidan
  • Eitan Friedman
Clinical Trial



Hereditary breast cancer is predominantly associated with germline mutations in the BRCA1 or BRCA2 genes. A few recurring mutations in these genes were reported in ethnically diverse Jewish populations. Since 2013, most oncogenetic laboratories in Israel adopted a two-step approach for BRCA1/2 genotyping, where the first step is genotyping for 14 seemingly recurring mutations—first-pass genotyping. The aim of this study was to assess the yield of this targeted BRCA sequencing.


Clinical and genotyping data of all individuals who underwent oncogenetic counseling and first-pass BRCA genotyping at the Oncogenetic Service Sheba and Assaf Harofeh Medical Centers from 1 February 2013 to 30 June 2017 were reviewed. All study participants were unrelated to each other.


Overall, 5152 oncogenetic tests were reviewed in the present study, of which 4452 had no a priori known familial mutation. The majority of participants (68.6%) were genotyped because of personal history of cancer; 20.6% were tested because of family history of cancer, and details for the remaining 10.7% were missing. Overall, 256/4452 (5.8%) carriers were detected, 141 BRCA1 and 115 BRCA2 mutation carriers. In 54% of cancer-free carriers, no clinically suspicious family history of cancer was ascertained.


The currently used scheme of first-pass genotyping in Israel seems to have a high yield of mutation detection even in the absence of a significant family history of cancer. The challenge is to optimize the currently used targeted panel of common mutations and adjust it to the accumulating new data in the Israeli population.


BRCA1 BRCA2 germline mutations First-pass genotyping Unselected screening Hereditary breast cancer 


Conflict of interest

All authors declare that they have no conflict of interest.


  1. 1.
    Warner E, Foulkes W, Goodwin P, Meschino W, Blondal J, Paterson C et al (1999) Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst 91:1241–1247CrossRefPubMedGoogle Scholar
  2. 2.
    Tobias DH, Eng C, McCurdy LD, Kalir T, Mandelli J, Dottino PR et al (2000) Founder BRCA 1 and 2 mutations among a consecutive series of Ashkenazi Jewish ovarian cancer patients. Gynecol Oncol 78:148–151CrossRefPubMedGoogle Scholar
  3. 3.
    Robson M, Dabney MK, Rosenthal G, Ludwig S, Seltzer MH, Gilewski T et al (1997) Prevalence of recurring BRCA mutations among Ashkenazi Jewish women with breast cancer. Genet Test 1:47–51PubMedGoogle Scholar
  4. 4.
    Lerer I, Wang T, Peretz T, Sagi M, Kaduri L, Orr-Urtreger A et al (1998) The 8765delAG mutation in BRCA2 is common among Jews of Yemenite extraction. Am J Hum Genet 63:272–274CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Shiri-Sverdlov R, Gershoni-Baruch R, Ichezkel-Hirsch G, Gotlieb WH, Bar-Sade RB, Chetrit A et al (2001) The Tyr978X BRCA1 mutation in non-Ashkenazi Jews: occurrence in high-risk families, general population and unselected ovarian cancer patients. Public Health Genomics 4:50–55CrossRefGoogle Scholar
  6. 6.
    Laitman Y, Simeonov M, Herskovitz L, Kushnir A, Shimon-Paluch S, Kaufman B et al (2012) Recurrent germline mutations in BRCA1 and BRCA2 genes in high risk families in Israel. Breast Cancer Res Treat 133:1153–1157CrossRefPubMedGoogle Scholar
  7. 7.
    Sagi M, Eilat A, Avi LB, Goldberg Y, Bercovich D, Hamburger T et al (2011) Two BRCA1/2 founder mutations in Jews of Sephardic origin. Fam Cancer 10:59–63CrossRefPubMedGoogle Scholar
  8. 8.
    Laitman Y, Borsthein RT, Stoppa-Lyonnet D, Dagan E, Castera L, Goislard M et al (2011) Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel. Breast Cancer Res Treat 127:489–495CrossRefPubMedGoogle Scholar
  9. 9.
    Parmigiani G, Berry D, Aguilar O (1998) Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet 62:145–158CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    The Penn II Risk model, BRCA 1 and BRCA 2 mutation predictor. Accessed 2 Sep 2017
  11. 11.
    Lee AJ, Cunningham AP, Kuchenbaecker KB, Mavaddat N, Easton DF, Antoniou AC (2014) BOADICEA breast cancer risk prediction model: updates to cancer incidences, tumour pathology and web interface. Br J Cancer 110:535–545CrossRefPubMedGoogle Scholar
  12. 12.
    Schayek H, De Marco L, Starinsky-Elbaz S, Rossette M, Laitman Y, Bastos-Rodrigues L et al (2016) The rate of recurrent BRCA1, BRCA2, and TP53 mutations in the general population, and unselected ovarian cancer cases, in Belo Horizonte, Brazil. Cancer Genet 209:50–52CrossRefPubMedGoogle Scholar
  13. 13.
    Zick A, Cohen S, Hamburger T, Goldberg Y, Zvi N, Sagi M et al (2015) A BRCA1 frame shift mutation in women of Kurdish Jewish descent. Open Med J. Google Scholar
  14. 14.
    Zick A, Kadouri L, Cohen S, Frohlinger M, Hamburger T, Zvi N et al (2017) Recurrent TP53 missense mutation in cancer patients of Arab descent. Fam Cancer 16:295–301CrossRefPubMedGoogle Scholar
  15. 15.
    Zidan J, Zhou AY, van den Akker J, Laitman Y, Schayek H, Schnaider J et al (2017) Inherited predisposition to breast and ovarian cancer in non-Jewish populations in Israel. Breast Cancer Res Treat. Google Scholar
  16. 16.
    Shaag A, Walsh T, Renbaum P, Kirchhoff T, Nafa K, Shiovitz S et al (2005) Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. Hum Mol Genet 14:555–563CrossRefPubMedGoogle Scholar
  17. 17.
    Walsh T, Mandell JB, Norquist BM, Casadei S, Gulsuner S, Lee MK et al (2017) Genetic predisposition to breast cancer due to mutations other than BRCA1 and BRCA2 founder alleles among Ashkenazi Jewish women. JAMA Oncol. Google Scholar
  18. 18.
    Janavičius R (2010) Founder BRCA1/2 mutations in the Europe: implications for hereditary breast–ovarian cancer prevention and control. EPMA J 1:397–412CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Weitzel JN, Lagos VI, Cullinane CA, Gambol PJ, Culver JO, Blazer KR et al (2007) Limited family structure and BRCA gene mutation status in single cases of breast cancer. JAMA 297:2587–2595CrossRefPubMedGoogle Scholar
  20. 20.
    King M-C, Marks JH, Mandell JB (2003) Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302:643–646CrossRefPubMedGoogle Scholar
  21. 21.
    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 64:963–970CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K et al (2015) Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer 121:25–33CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Rinat Bernstein-Molho
    • 1
    • 4
  • Yael Laitman
    • 2
  • Hagit Schayek
    • 2
  • Orit Reish
    • 3
    • 4
  • Shira Lotan
    • 3
  • Sara Haim
    • 3
  • Jamal Zidan
    • 5
    • 6
  • Eitan Friedman
    • 2
    • 4
  1. 1.Breast Cancer Center, Oncology InstituteChaim Sheba Medical CenterRamat GanIsrael
  2. 2.Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human GeneticsChaim Sheba Medical CenterRamat GanIsrael
  3. 3.Genetic InstituteAssaf Harofeh Medical CenterZerifinIsrael
  4. 4.Sackler School of MedicineTel-Aviv UniversityTel AvivIsrael
  5. 5.The Oncology DivisionZiv Medical CenterSafedIsrael
  6. 6.Faculty of Medicine in the GalileeBar-Ilan UniversitySafedIsrael

Personalised recommendations