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Counselling framework for moderate-penetrance cancer-susceptibility mutations

Abstract

The use of multigene panels for the assessment of cancer susceptibility is expanding rapidly in clinical practice, particularly in the USA, despite concerns regarding the uncertain clinical validity for some gene variants and the uncertain clinical utility of most multigene panels. So-called 'moderate-penetrance' gene mutations associated with cancer susceptibility are identified in approximately 2–5% of individuals referred for clinical testing; some of these mutations are potentially actionable. Nevertheless, the appropriate management of individuals harbouring such moderate-penetrance genetic variants is unclear. The cancer risks associated with mutations in moderate-penetrance genes are lower and different than those reported for high-penetrance gene mutations (such as mutations in BRCA1 and BRCA2, and those associated with Lynch syndrome). The extrapolation of guidelines for the management of individuals with high-penetrance variants of cancer-susceptibility genes to the clinical care of patients with moderate-penetrance gene mutations could result in substantial harm. Thus, we provide a framework for clinical decision-making pending the development of a sufficient evidence base to document the clinical utility of the interventions for individuals with inherited moderate-penetrance gene mutations associated with an increased risk of cancer.

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Acknowledgements

The authors wish to acknowledge Dr Emily Sonnenblick for critical review and comments on the breast cancer screening component of this analysis.

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Contributions

N.T., S.M.D. and M.E.R. researched the data and wrote the article. All authors made a substantial contribution to discussion of the content for the article, and reviewed and edited the manuscript before submission.

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Correspondence to Mark E. Robson.

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Competing interests

M.E.R. and J.G. receive research support from Myriad Genetics. The other authors declare no competing interests.

Supplementary information

Supplementary Table S1 (table)

Results of panel testing (PDF 206 kb)

Supplementary Table S2 (table)

Impact of variation in RR with age on cumulative risk estimates (PDF 196 kb)

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Tung, N., Domchek, S., Stadler, Z. et al. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol 13, 581–588 (2016). https://doi.org/10.1038/nrclinonc.2016.90

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