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Cancer genetics
Original research
Contribution of large genomic rearrangements in PALB2 to familial breast cancer: implications for genetic testing
  1. Na Li1,2,3,
  2. Magnus Zethoven2,4,
  3. Simone McInerny1,
  4. Eliza Healey1,
  5. Dilanka DeSilva2,3,
  6. Lisa Devereux3,5,
  7. Rodney J Scott6,7,8,
  8. Paul A James1,3,
  9. Ian G Campbell2,3
  1. 1 Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia
  2. 2 Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  3. 3 Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
  4. 4 Bioinformatics Core Facility, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  5. 5 Lifepool, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  6. 6 School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia
  7. 7 Division of Molecular Medicine, Pathology North, Newcastle, New South Wales, Australia
  8. 8 Discipline of Medical Genetics, The University of Newcastle and Hunter Medical Research Institute, Newcastle, New South Wales, Australia
  1. Correspondence to Dr Ian G Campbell, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; ian.campbell{at}petermac.org

Abstract

Background PALB2 is the most important contributor to familial breast cancer after BRCA1 and BRCA2. Large genomic rearrangements (LGRs) in BRCA1 and BRCA2 are routinely assessed in clinical testing and are a significant contributor to the yield of actionable findings. In contrast, the contribution of LGRs in PALB2 has not been systematically studied.

Methods We performed targeted sequencing and real-time qPCR validation to identify LGRs in PALB2 in 5770 unrelated patients with familial breast cancer and 5741 cancer-free control women from the same Australian population.

Results Seven large deletions ranging in size from 0.96 kbp to 18.07 kbp involving PALB2 were identified in seven cases, while no LGRs were identified in any of the controls. Six LGRs were considered pathogenic as they included one or more exons of PALB2 and disrupted the WD40 domain at the C terminal end of the PALB2 protein while one LGR only involved a partial region of intron 10 and was considered a variant of unknown significance. Altogether, pathogenic LGRs identified in this study accounted for 10.3% (6 of 58) of the pathogenic PALB2 variants detected among the 5770 families with familial breast cancer.

Conclusions Our data show that a clinically important proportion of PALB2 pathogenic mutations in Australian patients with familial breast cancer are LGRs. Such observations have provided strong support for inclusion of PALB2 LGRs in routine clinical genetic testing.

  • genetic testing
  • women's health
  • germ-line mutation
  • medical oncology
  • genetic variation

Data availability statement

Data are available on reasonable request. Original or source data in the paper are available on request to corresponding author.

https://doi.org/10.1136/jmedgenet-2021-108399

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    Data availability statement

    Data are available on reasonable request. Original or source data in the paper are available on request to corresponding author.

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    Footnotes

    • PAJ and IGC contributed equally.

    • Contributors IGC and PJ contributed equally to this paper. NL contributed to study design, generating sequencing libraries, data analysis and manuscript writing. MZ contributed to bioinformatic analysis and plotting. DDS contributed to data validation and clinical interpretation. EH contributed to performing real-time qPCR experiments. SM and LD contributed to collection of study materials or patients. RJS contributed to provision of patients’ material and data interpretation. PJ contributed to study design, clinical interpretation and manuscript revision. IGC contributed to study design, data analysis and manuscript revision and is responsible for the overall content as the guarantor . All authors contributed to drafting, revising and final approval of the manuscript.

    • Funding This work was supported by the National Breast Cancer Foundation (IF-15-004, IGC and PJ), Cancer Australia/National Breast Cancer Foundation (PdCCRS_1107870, IGC and PJ), the Victorian Cancer Agency (Tumor Stream Grant, PJ) and the National Health and Medical Research Council of Australia (GNT1023698, PJ; GNT1041975, IGC). NL is supported by fellowship from Cancer Council Victoria.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.