Familial Cancer

, Volume 17, Issue 4, pp 495–505 | Cite as

Clinical interpretation of pathogenic ATM and CHEK2 variants on multigene panel tests: navigating moderate risk

  • Allison H. West
  • Kathleen R. Blazer
  • Jessica Stoll
  • Matthew Jones
  • Caroline M. Weipert
  • Sarah M. Nielsen
  • Sonia S. Kupfer
  • Jeffrey N. Weitzel
  • Olufunmilayo I. OlopadeEmail author
Original Article


Comprehensive genomic cancer risk assessment (GCRA) helps patients, family members, and providers make informed choices about cancer screening, surgical and chemotherapeutic risk reduction, and genetically targeted cancer therapies. The increasing availability of multigene panel tests for clinical applications allows testing of well-defined high-risk genes, as well as moderate-risk genes, for which the penetrance and spectrum of cancer risk are less well characterized. Moderate-risk genes are defined as genes that, when altered by a pathogenic variant, confer a 2 to fivefold relative risk of cancer. Two such genes included on many comprehensive cancer panels are the DNA repair genes ATM and CHEK2, best known for moderately increased risk of breast cancer development. However, the impact of screening and preventative interventions and spectrum of cancer risk beyond breast cancer associated with ATM and/or CHEK2 variants remain less well characterized. We convened a large, multidisciplinary, cross-sectional panel of GCRA clinicians to review challenging, peer-submitted cases of patients identified with ATM or CHEK2 variants. This paper summarizes the inter-professional case discussion and recommendations generated during the session, the level of concordance with respect to recommendations between the academic and community clinician participants for each case, and potential barriers to implementing recommended care in various practice settings.


Cancer genetics ATM CHEK2 Moderate-risk gene Panel test Genomic cancer risk assessment (GCRA) 



Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R13CA206594-01 (PI: O. Olopade) and R25CA171998 (PIs: K. Blazer and J. Weitzel). A. West is supported by the National Cancer Institute of the National Institutes of Health under a Basic Medical Research Training in Oncology Award Number T32CA009566 (PI: O. Olopade). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Compliance with ethical standards

Conflict of interest

Dr. Olufunmilayo Olopade is co-founder of CancerIQ. All co-authors declare that they have no conflict of interest.

Supplementary material

10689_2018_70_MOESM1_ESM.pdf (417 kb)
Cancer Genetics and Genomics Conference syllabus. (PDF 417 KB)
10689_2018_70_MOESM2_ESM.pdf (48 kb)
Participant survey. (PDF 47 KB)


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Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  • Allison H. West
    • 1
  • Kathleen R. Blazer
    • 2
  • Jessica Stoll
    • 3
    • 4
  • Matthew Jones
    • 5
  • Caroline M. Weipert
    • 3
  • Sarah M. Nielsen
    • 3
  • Sonia S. Kupfer
    • 3
    • 5
  • Jeffrey N. Weitzel
    • 2
  • Olufunmilayo I. Olopade
    • 1
    • 3
    Email author
  1. 1.Section of Hematology/OncologyThe University of Chicago Comprehensive Cancer CenterChicagoUSA
  2. 2.Division of Clinical Cancer GenomicsCity of Hope Comprehensive Cancer Center and Beckman Research InstituteDuarteUSA
  3. 3.Department of Medicine, Center for Clinical Cancer GeneticsThe University of ChicagoChicagoUSA
  4. 4.Department of Medicine, Section of Gastroenterology, Hepatology and NutritionUniversity of ChicagoChicagoUSA
  5. 5.Pritzker School of MedicineUniversity of ChicagoChicagoUSA

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