Management of individuals with heterozygous germline pathogenic variants in RAD51C, RAD51D, and BRIP1: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

Joanne Ngeow¹, Jianbang Chiang¹, Esteban Astiazaran-Symonds², Judith Balmaña³, Ilana Cass⁴, Felix K F Kommoss⁵, William D Foulkes⁶, Paul A James⁷, Arielle Katcher⁸, Susan Klugman⁹, Alicia A Livinski¹⁰, Julie S Mak¹¹, Nicoleta Voian¹², Myra J Wick¹³, Marc Tischkowitz¹⁴, Tuya Pal¹⁵, Douglas R Stewart¹⁶, Helen Hanson¹⁷; ACMG Professional Practice and Guidelines Committee. Electronic address: documents@acmg.net¹⁸

Affiliations

¹ Genomic Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
² Department of Medicine, College of Medicine-Tucson, University of Arizona, Tucson, AZ.
³ Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Medical Oncology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Hospital Campus, Barcelona, Spain.
⁴ Department of Obstetrics and Gynecology, Geisel School of Medicine, Dartmouth-Hitchcock Health, Lebanon, NH.
⁵ Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
⁶ Departments of Human Genetics, Oncology and Medicine, McGill University, Montréal, Québec, Canada.
⁷ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia; Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, Melbourne, Victoria, Australia.
⁸ Division of Gynecologic Oncology, Helen F. Graham Cancer Center, ChristianaCare Health System, Newark, DE.
⁹ Division of Reproductive and Medical Genetics, Department of Obstetrics & Gynecology and Women's Health, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY.
¹⁰ National Institutes of Health Library, Office of Research Services, OD, NIH, Bethesda, MD.
¹¹ University of California San Francisco Health Center for Clinical Genetics and Genomics, San Francisco, CA.
¹² Providence Genetic Risk Clinic, Providence Cancer Institute, Portland, OR.
¹³ Departments of Obstetrics and Gynecology and Clinical Genomics, Mayo Clinic, Rochester, MN.
¹⁴ Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
¹⁵ Department of Medicine, Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, TN.
¹⁶ Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.
¹⁷ Peninsula Clinical Genetics, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK; Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK.
¹⁸ American College of Medical Genetics and Genomics, Bethesda, MD.

PMID: 41070818
DOI: 10.1016/j.gim.2025.101557

Practice Guideline

Management of individuals with heterozygous germline pathogenic variants in RAD51C, RAD51D, and BRIP1: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

Joanne Ngeow et al. Genet Med. 2025 Nov.

. 2025 Nov;27(11):101557.

doi: 10.1016/j.gim.2025.101557. Epub 2025 Oct 7.

Authors

Affiliations

¹ Genomic Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
² Department of Medicine, College of Medicine-Tucson, University of Arizona, Tucson, AZ.
³ Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Medical Oncology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Hospital Campus, Barcelona, Spain.
⁴ Department of Obstetrics and Gynecology, Geisel School of Medicine, Dartmouth-Hitchcock Health, Lebanon, NH.
⁵ Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
⁶ Departments of Human Genetics, Oncology and Medicine, McGill University, Montréal, Québec, Canada.
⁷ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia; Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, Melbourne, Victoria, Australia.
⁸ Division of Gynecologic Oncology, Helen F. Graham Cancer Center, ChristianaCare Health System, Newark, DE.
⁹ Division of Reproductive and Medical Genetics, Department of Obstetrics & Gynecology and Women's Health, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY.
¹⁰ National Institutes of Health Library, Office of Research Services, OD, NIH, Bethesda, MD.
¹¹ University of California San Francisco Health Center for Clinical Genetics and Genomics, San Francisco, CA.
¹² Providence Genetic Risk Clinic, Providence Cancer Institute, Portland, OR.
¹³ Departments of Obstetrics and Gynecology and Clinical Genomics, Mayo Clinic, Rochester, MN.
¹⁴ Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
¹⁵ Department of Medicine, Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, TN.
¹⁶ Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.
¹⁷ Peninsula Clinical Genetics, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK; Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK.
¹⁸ American College of Medical Genetics and Genomics, Bethesda, MD.

PMID: 41070818
DOI: 10.1016/j.gim.2025.101557

Abstract

Purpose: RAD51C, RAD51D, and BRIP1 germline pathogenic variants (GPVs) are associated with increased lifetime risks of tubo-ovarian cancer. Resources for managing RAD51C, RAD51D, and BRIP1 heterozygotes in clinical practice are limited.

Methods: An international workgroup developed a Clinical Practice Resource to guide management of RAD51C, RAD51D, and BRIP1 heterozygotes using peer-reviewed publications and expert opinion.

Results: RAD51C, RAD51D, and BRIP1 are moderate (intermediate) penetrance ovarian cancer predisposition genes. Ovarian cancer risks for individuals with RAD51C, RAD51D, and BRIP1 GPVs may be influenced by family history and other modifiers. RAD51C and RAD51D GPVs are also associated with moderate risk of breast cancer, predominantly triple-negative subtype. RAD51C, RAD51D, and BRIP1 heterozygotes should be offered risk-reducing salpingo-oophorectomy close to the age of menopause based on age-specific risks and shared decision making. For RAD51C and RAD51D heterozygotes, enhanced breast surveillance may be indicated according to their personalized risk estimate and country-specific guidelines. Generally, risk-reducing mastectomy is not recommended. For RAD51C, RAD51D, and BRIP1 heterozygotes who develop cancer, there is insufficient evidence to guide any specific targeted treatment.

Conclusion: Systematic prospective data collection is needed to establish the outcomes of RAD51C, RAD51D, and BRIP1 associated cancers and particularly response to cancer treatment and survival.

Keywords: BRIP1; Cancer predisposition; Cancer risk; RAD51C; RAD51D.

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Conflict of interest statement

Conflict of Interest Funding and support listed here did not support development of this document unless included in the acknowledgments section. All workgroup members receive salary for providing clinical services that may be relevant to the content of this document in either the laboratory or patient care setting at their listed affiliations. The following workgroup members have additional conflicts of interest: J.N. (AstraZeneca [research and education grants], Nalagenetics, Nanopore, and Pacbio [research funding]); M.T. (National Institute for Health, Care Research Cambridge Biomedical Research Centre [research funding]); T.P. (National Cancer Institute, Komen Foundation, Breast Cancer Research Foundation [research funding]); D.R.S. (Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, Genome Medical, Inc [contract clinical telehealth services]); H.H. (Cancer Research CRUK Catalyst Award, CanGene-CanVar, the National Institute for Health and Care Research Exeter Biomedical Research Centre [research funding] and AstraZeneca [advisory board]). All other authors declare no conflicts of interest.

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Management of individuals with heterozygous germline pathogenic variants in RAD51C, RAD51D, and BRIP1: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

Affiliations

Management of individuals with heterozygous germline pathogenic variants in RAD51C, RAD51D, and BRIP1: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

Authors

Affiliations

Abstract

Conflict of interest statement

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Full Text Sources

Medical

Research Materials

Miscellaneous