Article Text

Original article
Multigene testing of moderate-risk genes: be mindful of the missense
  1. E L Young1,
  2. B J Feng2,
  3. A W Stark1,
  4. F Damiola3,
  5. G Durand4,
  6. N Forey4,
  7. T C Francy1,
  8. A Gammon5,
  9. W K Kohlmann5,
  10. K A Kaphingst6,
  11. S McKay-Chopin4,
  12. T Nguyen-Dumont7,
  13. J Oliver8,
  14. A M Paquette1,
  15. M Pertesi4,
  16. N Robinot4,
  17. J S Rosenthal1,
  18. M Vallee9,
  19. C Voegele4,
  20. J L Hopper10,11,
  21. M C Southey6,
  22. I L Andrulis12,
  23. E M John13,14,
  24. M Hashibe15,
  25. J Gertz1,
  26. Breast Cancer Family Registry13,
  27. F Le Calvez-Kelm4,
  28. F Lesueur16,
  29. D E Goldgar2,
  30. S V Tavtigian1
  1. 1Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, USA
  2. 2Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, USA
  3. 3Breast Cancer Genetics Group, Cancer Research Centre of Lyon, Centre Léon Bérard, Lyon, France
  4. 4Genetic Cancer Susceptibility group, International Agency for Research on Cancer, Lyon, France
  5. 5Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, USA
  6. 6Department of Communication and Huntsman Cancer Institute, University of Utah
  7. 7Genetic Epidemiology Laboratory, The University of Melbourne, Melbourne, Victoria, Australia
  8. 8Instituto de Ciencias Básicas y Medicina Experimental del Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
  9. 9Cancer Genomics Laboratory, CHUQ Research Center, Quebec City, Canada
  10. 10Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
  11. 11Department of Epidemiology (Genome Epidemiology Lab), Seoul National University School of Public Health, Seoul, Korea
  12. 12Department of Molecular Genetics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
  13. 13Cancer Prevention Institute of California, Fremont, California, USA
  14. 14Department of Health Research and Policy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA
  15. 15Department of Family and Preventive Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, USA
  16. 16Genetic Epidemiology of Cancer Team, Inserm, U900, Institut Curie, Paris, France
  1. Correspondence to Professor Sean V Tavtigian, Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA; sean.tavtigian{at}


Background Moderate-risk genes have not been extensively studied, and missense substitutions in them are generally returned to patients as variants of uncertain significance lacking clearly defined risk estimates. The fraction of early-onset breast cancer cases carrying moderate-risk genotypes and quantitative methods for flagging variants for further analysis have not been established.

Methods We evaluated rare missense substitutions identified from a mutation screen of ATM, CHEK2, MRE11A, RAD50, NBN, RAD51, RINT1, XRCC2 and BARD1 in 1297 cases of early-onset breast cancer and 1121 controls via scores from Align-Grantham Variation Grantham Deviation (GVGD), combined annotation dependent depletion (CADD), multivariate analysis of protein polymorphism (MAPP) and PolyPhen-2. We also evaluated subjects by polygenotype from 18 breast cancer risk SNPs. From these analyses, we estimated the fraction of cases and controls that reach a breast cancer OR≥2.5 threshold.

Results Analysis of mutation screening data from the nine genes revealed that 7.5% of cases and 2.4% of controls were carriers of at least one rare variant with an average OR≥2.5. 2.1% of cases and 1.2% of controls had a polygenotype with an average OR≥2.5.

Conclusions Among early-onset breast cancer cases, 9.6% had a genotype associated with an increased risk sufficient to affect clinical management recommendations. Over two-thirds of variants conferring this level of risk were rare missense substitutions in moderate-risk genes. Placement in the estimated OR≥2.5 group by at least two of these missense analysis programs should be used to prioritise variants for further study. Panel testing often creates more heat than light; quantitative approaches to variant prioritisation and classification may facilitate more efficient clinical classification of variants.

  • Cancer: breast
  • Clinical genetics
  • Genetics
  • Screening

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.