Clinical interpretation of pathogenic ATM and CHEK2 variants on multigene panel tests: navigating moderate risk
- 903 Downloads
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.
KeywordsCancer 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.
- 1.Hodgson SV (2007) A practical guide to human cancer genetics, 3rd edn. Cambridge University Press, New YorkGoogle Scholar
- 3.Offit K (1998) Clinical cancer genetics: risk counseling and management New York. Wiley Liss, New YorkGoogle Scholar
- 7.National Comprehensive Cancer Network (NCCN) (2016). Genetic/familial high-risk assessment: breast and ovarian version 2Google Scholar
- 14.National Comprehensive Cancer Network (NCCN) (2015). Genetic/familial high-risk assessment: colorectal. Version 2Google Scholar
- 24.Kapoor NS, Curcio LD, Blakemore CA et al (2015) Multigene panel testing detects equal rates of pathogenic BRCA1/2 mutations and has a higher diagnostic yield compared to limited BRCA1/2 analysis alone in patients at risk for hereditary breast cancer. Ann Surg Oncol 22(10):3282–3288. https://doi.org/10.1245/s10434-015-4754-2 CrossRefPubMedGoogle Scholar
- 27.Microsoft Excel (2013) Microsoft, RedmondGoogle Scholar
- 28.Creswell JW (2003) Mixed Methods procedures. Research design qualitative, quantitative, and mixed method approaches, 2nd edn. Sage, Thousand Oaks, pp 208–225Google Scholar
- 31.National Comprehensive Cancer Network (NCCN) (2017) Breast Cancer Screening and Diagnosis. Version 1Google Scholar
- 39.National Comprehensive Cancer Network (NCCN) (2018). Genetic/familial high-risk assessment: breast and ovarian Version 1Google Scholar
- 40.Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, Hoover J, Jang W, Katz K, Ovetsky M, Riley G, Sethi A, Tully R, Villamarin-Salomon R, Rubinstein W, Maglott DR (2015) ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res 44(D1):D862–D868CrossRefGoogle Scholar
- 41.National Comprehensive Cancer Network (NCCN) (2017) Genetic/familial high-risk assessment: colorectal Version 3Google Scholar
- 42.Boughey JC, Attai DJ, Chen SL et al (2016) contralateral prophylactic mastectomy (CPM) consensus statement from the American Society of Breast Surgeons: data on CPM outcomes and risks. Ann Surg Oncol 23(10):3100–3105. https://doi.org/10.1245/s10434-016-5443-5 CrossRefPubMedPubMedCentralGoogle Scholar
- 44.Giuliano AE, Boolbol S, Degnim A, Kuerer H, Leitch AM, Morrow M (2007) Society of Surgical Oncology: position statement on prophylactic mastectomy. Approved by the Society of Surgical Oncology Executive Council, March 2007. Ann Surg Oncol 14(9):2425–2427. https://doi.org/10.1245/s10434-007-9447-z CrossRefPubMedGoogle Scholar
- 47.Brandberg Y, Sandelin K, Erikson S et al (2008) Psychological reactions, quality of life, and body image after bilateral prophylactic mastectomy in women at high risk for breast cancer: a prospective 1-year follow-up study. J Clin Oncol 26(24):3943–3949. https://doi.org/10.1200/jco.2007.13.9568 CrossRefPubMedGoogle Scholar
- 49.den Heijer M, Seynaeve C, Timman R et al (2012) Body image and psychological distress after prophylactic mastectomy and breast reconstruction in genetically predisposed women: a prospective long-term follow-up study. Eur J Cancer 48(9):1263-8. https://doi.org/10.1016/j.ejca.2011.10.020 CrossRefGoogle Scholar
- 50.National Institutes of Health (2018) All of Us Research ProgramGoogle Scholar