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Penetrance estimates for BRCA1, BRCA2 (also applied to Lynch syndrome) based on presymptomatic testing: a new unbiased method to assess risk?
  1. D Gareth Evans1,2,3,
  2. Emma Woodward2,
  3. Elaine F Harkness3,4,
  4. Anthony Howell3,5,
  5. Inga Plaskocinska6,
  6. Eamonn R Maher6,
  7. Marc D Tischkowitz6,
  8. Fiona Lalloo2
  1. 1 Division of Evolution and Genomic Science, Manchester Centre for Genomic Medicine, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
  2. 2 Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester, UK
  3. 3 Prevent Breast Cancer Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK
  4. 4 Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
  5. 5 Department of Medical Oncology, Christie Hospital, Manchester, UK
  6. 6 Department of Medical Genetics, Cancer Research UK Cambridge Centre, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
  1. Correspondence to Professor D Gareth Evans, Manchester Centre for Genomic Medicine, St. Mary’s Hospital, Manchester M13 9WL, UK; gareth.evans{at}


Purpose The identification of BRCA1, BRCA2 or mismatch repair (MMR) pathogenic gene variants in familial breast/ovarian/colorectal cancer families facilitates predictive genetic testing of at-risk relatives. However, controversy still exists regarding overall lifetime risks of cancer in individuals testing positive.

Methods We assessed the penetrance of BRCA1, BRCA2, MLH1 and MSH2 mutations in men and women using Bayesian calculations based on ratios of positive to negative presymptomatic testing by 10-year age cohorts. Mutation position was also assessed for BRCA1/BRCA2.

Results Using results from 2264 presymptomatic tests in first-degree relatives (FDRs) of mutation carriers in BRCA1 and BRCA2 and 646 FDRs of patients with MMR mutations, we assessed overall associated cancer penetrance to age of 68 years as 73% (95% CI 61% to 82%) for BRCA1, 60% (95% CI 49% to 71%) for BRCA2, 95% (95% CI 76% to 99%) for MLH1% and 61% (95% CI 49% to 76%) for MSH2. There was no evidence for significant penetrance for males in BRCA1 or BRCA2 families and males had equivalent penetrance to females with Lynch syndrome. Mutation position and degree of family history influenced penetrance in BRCA2 but not BRCA1.

Conclusion We describe a new method for assessing penetrance in cancer-prone syndromes. Results are in keeping with published prospective series and present modern-day estimates for overall disease penetrance that bypasses retrospective series biases.

  • brca1
  • brca2
  • penetrance
  • Lynch syndrome
  • pre-symptomatic

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  • Contributors DGE: conception; DGE, EW, FL, MDT, IP: data collection; DGE, EFH: data analysis; all: manuscript writing and approval of final version.

  • Funding DGE acknowledges support from the all Manchester NIHR Biomedical Research Centre and as an NIHR Senior Investigator. MDT acknowledges support from the European Union Seventh Framework Program (2007Y2013)/European Research Council (grant number 310018) and the Cancer Research UK Cambridge Centre Early Detection Programme (CRUK grant ref: A20976). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR Senior Investigator Award and Cambridge NIHR Biomedical Research Centre and Cancer Research UK Cambridge Cancer Centre. The University of Cambridge has received salary support in respect of ERM from the NHS in the East of England through the Clinical Academic Reserve.

  • Disclaimer The views expressed are those of the authors and not necessarily those of the NHS or Department of Health.

  • Competing interests DGE has received a bursary from AstraZeneca for travel to a conference round table on MEK inhibitors not relevant to this publication.

  • Patient consent Not required.

  • Ethics approval The study was carried out with Local Ethical Committee approval.

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

  • Data sharing statement Unpublished raw data is available on request.