Unrecognised actionability for breast cancer risk variants identified in a national-level review of Australian familial cancer centres

Cristina Fortuno¹, Elisa J Cops², Aimee L Davidson¹, Johanna Hadler¹, Giovanni Innella³, Maddison E McKenzie¹, Michael Parsons¹, Ainsley M Campbell⁴, Andrew Dubowsky^{5

6}, Verna Fargas⁷, Michael J Field⁸, Helen G Mar Fan^{9

10}, Cassandra B Nichols¹¹, Nicola K Poplawski^{12

13}, Linda Warwick¹⁴, Rachel Williams^{15

16}, Victoria Beshay¹⁷, Caitlin Edwards¹⁸, Andrea Johns¹⁹, Mary McPhillips¹⁹, Vanessa Siva Kumar²⁰, Rodney Scott^{19

21}, Mark Williams²², Hamish Scott^{5

13

23

24}, Paul A James^{2

25}, Amanda B Spurdle^{26

27}

Affiliations

¹ Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
² Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia.
³ Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy.
⁴ Department of Clinical Genetics, Austin Health, Melbourne, VIC, Australia.
⁵ Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.
⁶ College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.
⁷ Liverpool Cancer Genetics, Liverpool Hospital, Liverpool, NSW, Australia.
⁸ Family Cancer Clinic, Royal North Shore Hospital, St Leonards, NSW, Australia.
⁹ Genetic Health Queensland Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
¹⁰ Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
¹¹ Genetic Health WA, King Edward Memorial Hospital, Perth, WA, Australia.
¹² Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.
¹³ Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
¹⁴ ACT Genetic Service Canberra Health Services, Garran, ACT, Australia.
¹⁵ School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
¹⁶ Prince of Wales Hereditary Cancer Centre, Prince of Wales Hospital, Randwick, NSW, Australia.
¹⁷ Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
¹⁸ Diagnostic Genomics, Pathwest Laboratory Medicine, QEII Medical Centre, Nedlands, WA, Australia.
¹⁹ NSW Health Pathology, Newcastle, NSW, Australia.
²⁰ Invitae Australia, Sydney, NSW, Australia.
²¹ Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia.
²² Genomic Diagnostics, Melbourne, VIC, Australia.
²³ Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, SA, Australia.
²⁴ UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia.
²⁵ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
²⁶ Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. amanda.spurdle@qimrberghofer.edu.au.
²⁷ Faculty of Medicine, The University of Queensland, Herston, QLD, Australia. amanda.spurdle@qimrberghofer.edu.au.

PMID: 39402389
PMCID: PMC11607406
DOI: 10.1038/s41431-024-01705-9

Unrecognised actionability for breast cancer risk variants identified in a national-level review of Australian familial cancer centres

Cristina Fortuno et al. Eur J Hum Genet. 2024 Dec.

. 2024 Dec;32(12):1632-1639.

doi: 10.1038/s41431-024-01705-9. Epub 2024 Oct 14.

Authors

Affiliations

¹ Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
² Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia.
³ Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy.
⁴ Department of Clinical Genetics, Austin Health, Melbourne, VIC, Australia.
⁵ Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.
⁶ College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.
⁷ Liverpool Cancer Genetics, Liverpool Hospital, Liverpool, NSW, Australia.
⁸ Family Cancer Clinic, Royal North Shore Hospital, St Leonards, NSW, Australia.
⁹ Genetic Health Queensland Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
¹⁰ Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
¹¹ Genetic Health WA, King Edward Memorial Hospital, Perth, WA, Australia.
¹² Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.
¹³ Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
¹⁴ ACT Genetic Service Canberra Health Services, Garran, ACT, Australia.
¹⁵ School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
¹⁶ Prince of Wales Hereditary Cancer Centre, Prince of Wales Hospital, Randwick, NSW, Australia.
¹⁷ Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
¹⁸ Diagnostic Genomics, Pathwest Laboratory Medicine, QEII Medical Centre, Nedlands, WA, Australia.
¹⁹ NSW Health Pathology, Newcastle, NSW, Australia.
²⁰ Invitae Australia, Sydney, NSW, Australia.
²¹ Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia.
²² Genomic Diagnostics, Melbourne, VIC, Australia.
²³ Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, SA, Australia.
²⁴ UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia.
²⁵ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
²⁶ Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. amanda.spurdle@qimrberghofer.edu.au.
²⁷ Faculty of Medicine, The University of Queensland, Herston, QLD, Australia. amanda.spurdle@qimrberghofer.edu.au.

PMID: 39402389
PMCID: PMC11607406
DOI: 10.1038/s41431-024-01705-9

Abstract

Breast cancer remains a significant global health challenge. In Australia, the adoption of publicly-funded multigene panel testing for eligible cancer patients has increased accessibility to personalised care, yet has also highlighted the increasing prevalence of variants of uncertain significance (VUS), complicating clinical decision-making. This project aimed to explore the spectrum and actionability of breast cancer VUS in Australian familial cancer centers (FCCs). Leveraging data from 11 FCCs participating in the Inherited Cancer Connect database, we retrieved VUS results from 1472 patients. Through ClinVar crosschecks and application of gene-specific ACMG/AMP guidelines, we showed the potential for reclassification of 4% of unique VUS as pathogenic or likely pathogenic, and 80% as benign or likely benign. Surveys conducted with FCCs and diagnostic laboratories described current practices and challenges in variant reclassifications, highlighting resource constraints preventing periodic VUS review and notifications from the laboratories to the FCCs. Our study suggests there are benefits to routine VUS review and reclassification, particularly in publicly-funded healthcare systems. Future research should focus on assessing the clinical impact and cost-effectiveness of implementing routine variant review practices, alongside efforts to enhance communication between FCCs and laboratories.

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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethical approval: This project has been approved by the QIMR Berghofer Medical Research Institute Human Research Ethics Committee (HREC) under QIMR HREC Approval P1051.

Figures

Fig. 1. Overview of the process followed in this study to retrieve and review breast cancer VUS identified from FCC clinical databases for unrecognised actionability, and to understand processes limiting VUS review and reclassification.
ACMG/AMP American College of Medical Genetics and Genomics/Association for Molecular Pathology, FCC Familial cancer centre, VUS Variant of uncertain significance.

**Fig. 2. Results from the ClinVar crosscheck for 944 unique breast cancer VUS retrieved from FCCs according to the review status and designated summary classification.**
B/LB Benign/Likely benign, P/LP Pathogenic/Likely pathogenic.

**Fig. 3. Suggested number of variant reclassifications as P/LP or B/LB out of the 713 VUS reviewed using gene-specific ACMG/AMP guidelines.**
B/LB Benign/Likely benign, P/LP Pathogenic/Likely pathogenic.

See this image and copyright information in PMC

References

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Unrecognised actionability for breast cancer risk variants identified in a national-level review of Australian familial cancer centres

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Unrecognised actionability for breast cancer risk variants identified in a national-level review of Australian familial cancer centres

Authors

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Abstract

Conflict of interest statement

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