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Purpose: Although the role of CHEK2 germline pathogenic variants in cancer predisposition is well known, resources for managing CHEK2 heterozygotes in clinical practice are limited., Methods: An international workgroup developed guidance on clinical management of CHEK2 heterozygotes informed by peer-reviewed publications from PubMed., Results: Although CHEK2 is considered a moderate penetrance gene, cancer risks may be considered as a continuous variable, which are influenced by family history and other modifiers. Consequently, early cancer detection and prevention for CHEK2 heterozygotes should be guided by personalized risk estimates. Such estimates may result in both downgrading lifetime breast cancer risks to those similar to the general population or upgrading lifetime risk to a level at which CHEK2 heterozygotes are offered high-risk breast surveillance according to country-specific guidelines. Risk-reducing mastectomy should be guided by personalized risk estimates and shared decision making. Colorectal and prostate cancer surveillance should be considered based on assessment of family history. For CHEK2 heterozygotes who develop cancer, no specific targeted medical treatment is recommended at this time., Conclusion: Systematic prospective data collection is needed to establish the spectrum of CHEK2-associated cancer risks and to determine yet-unanswered questions, such as the outcomes of surveillance, response to cancer treatment, and survival after cancer diagnosis., Competing Interests: Conflict of Interest Funding and support listed here did not support development of this document unless included in the acknowledgments section. H.H. is supported by the Cancer Research CRUK Catalyst Award, CanGene-CanVar, and has served on advisory boards for AstraZeneca. R.S. is supported by the German Cancer Aid and the Federal Ministry of Education and Research (BMBF), Germany. M.T. is supported by the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre. D.R.S. is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute (NCI), Rockville, Maryland, and also performs contract clinical telehealth services for Genome Medical, Inc., in accordance with relevant NCI ethics policies. All other authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Purpose: PALB2 germline pathogenic variants are associated with increased breast cancer risk and smaller increased risk of pancreatic and likely ovarian cancer. Resources for health-care professionals managing PALB2 heterozygotes are currently limited., Methods: A workgroup of experts sought to outline management of PALB2 heterozygotes based on current evidence. Peer-reviewed publications from PubMed were identified to guide recommendations, which arose by consensus and the collective expertise of the authors., Results: PALB2 heterozygotes should be offered BRCA1/2-equivalent breast surveillance. Risk-reducing mastectomy can be considered guided by personalized risk estimates. Pancreatic cancer surveillance should be considered, but ideally as part of a clinical trial. Typically, ovarian cancer surveillance is not recommended, and risk-reducing salpingo-oophorectomy should only rarely be considered before the age of 50. Given the mechanistic similarities, PALB2 heterozygotes should be considered for therapeutic regimens and trials as those for BRCA1/2., Conclusion: This guidance is similar to those for BRCA1/2. While the range of the cancer risk estimates overlap with BRCA1/2, point estimates are lower in PALB2 so individualized estimates are important for management decisions. Systematic prospective data collection is needed to determine as yet unanswered questions such as the risk of contralateral breast cancer and survival after cancer diagnosis., (© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)