Breast Cancer Research and Treatment

, Volume 149, Issue 2, pp 547–554 | Cite as

Mutation screening of PALB2 in clinically ascertained families from the Breast Cancer Family Registry

  • Tú Nguyen-Dumont
  • Fleur Hammet
  • Maryam Mahmoodi
  • Helen Tsimiklis
  • Zhi L. Teo
  • Roger Li
  • Bernard J. Pope
  • Mary Beth Terry
  • Saundra S. Buys
  • Mary Daly
  • John L. Hopper
  • Ingrid Winship
  • David E. Goldgar
  • Daniel J. Park
  • Melissa C. Southey
Brief Report


Loss-of-function mutations in PALB2 are associated with an increased risk of breast cancer, with recent data showing that female breast cancer risks for PALB2 mutation carriers are comparable in magnitude to those for BRCA2 mutation carriers. This study applied targeted massively parallel sequencing to characterize the mutation spectrum of PALB2 in probands attending breast cancer genetics clinics in the USA. The coding regions and proximal intron–exon junctions of PALB2 were screened in probands not known to carry a mutation in BRCA1 or BCRA2 from 1,250 families enrolled through familial cancer clinics by the Breast Cancer Family Registry. Mutation screening was performed using Hi-Plex, an amplicon-based targeted massively parallel sequencing platform. Screening of PALB2 was successful in 1,240/1,250 probands and identified nine women with protein-truncating mutations (three nonsense mutations and five frameshift mutations). Four of the 33 missense variants were predicted to be deleterious to protein function by in silico analysis using two different programs. Analysis of tumors from carriers of truncating mutations revealed that the majority were high histological grade, invasive ductal carcinomas. Young onset was apparent in most families, with 19 breast cancers under 50 years of age, including eight under the age of 40 years. Our data demonstrate the utility of Hi-Plex in the context of high-throughput testing for rare genetic mutations and provide additional timely information about the nature and prevalence of PALB2 mutations, to enhance risk assessment and risk management of women at high risk of cancer attending clinical genetic services.


Breast cancer PALB2 Mutation screening Massively parallel sequencing Hi-Plex Genetic variant 

List of abbreviations


Breast Cancer Family Registry


Estrogen receptor


Human epithelial growth factor-2


Lymphoblastoid cell line


Leiden open variant database


Progesterone receptor



TN-D is a Susan G. Komen for the Cure Postdoctoral Fellow. ZLT was supported by Postgraduate Scholarships provided by the Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne and the National Health and Medical Research Council (NHMRC, Australia). RL is supported by UROP, a program of Biomedical Research Victoria, by the Victorian Life Sciences Computation Initiative (VLSCI) and by the Department of Pathology, The University of Melbourne. MCS is an NHMRC Senior Research Fellow. The Utah, New York, and Philadelphia sites of the Breast Cancer Family Registry were supported by Grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), or does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. This work was supported by the Australian National Health and Medical Research Council (NHMRC) (APP1025879 and APP1029974), the Victorian Breast Cancer Research Consortium and by a VLSCI Grant (number VR0182) on its Peak Computing Facility, an initiative of the Victorian Government.

Conflict of interests

The authors declare that they have no competing interests.


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Tú Nguyen-Dumont
    • 1
  • Fleur Hammet
    • 1
  • Maryam Mahmoodi
    • 1
  • Helen Tsimiklis
    • 1
  • Zhi L. Teo
    • 1
    • 2
  • Roger Li
    • 3
  • Bernard J. Pope
    • 3
    • 4
  • Mary Beth Terry
    • 5
    • 6
  • Saundra S. Buys
    • 7
  • Mary Daly
    • 8
  • John L. Hopper
    • 9
  • Ingrid Winship
    • 10
    • 11
  • David E. Goldgar
    • 7
  • Daniel J. Park
    • 1
  • Melissa C. Southey
    • 1
  1. 1.Genetic Epidemiology Laboratory, Department of PathologyThe University of MelbourneMelbourneAustralia
  2. 2.Peter MacCallum Cancer CentreEast MelbourneAustralia
  3. 3.Victorian Life Sciences Computation InitiativeMelbourneAustralia
  4. 4.Department of Computing and Information SystemsThe University of MelbourneMelbourneAustralia
  5. 5.Columbia University Mailman School of Public HealthNew YorkUSA
  6. 6.Herbert Irving Comprehensive Cancer CenterNew YorkUSA
  7. 7.Huntsman Cancer InstituteSalt Lake CityUSA
  8. 8.Fox Chase Cancer CenterPhiladelphiaUSA
  9. 9.Centre for Epidemiology and StatisticsThe University of MelbourneCarltonAustralia
  10. 10.Department of MedicineThe University of Melbourne HealthParkvilleAustralia
  11. 11.The Royal Melbourne HospitalParkvilleAustralia

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