RAD51D-Related Cancer Risk
The RAD51D gene plays a role in how DNA repairs itself.
The RAD51D gene is classified as a “moderate risk” gene, meaning that there is a modestly increased risk for certain types of cancers. For example, women who have one RAD51D pathogenic gene mutation have a relative risk for ovarian cancer of 12 compared to the general population. RAD51D gene mutations have also been linked to an increased risk of prostate cancer, but the lifetime risks for prostate cancer is not yet defined. Further research is needed to understand the interactions of moderate risk genes and family history on lifetime cancer risk.
RAD51D cancer screening and risk-reducing options
There is currently no agreement within the medical community on the best long-term medical management for an individual who carries a mutation in the RAD51D gene. Healthcare providers oftentimes rely on an individual’s personal and family history to guide medical care. Women with mutations in RAD51D should not undergo MRI screening based on the presence of the mutation in one of these genes alone.
NCCN and PROMPT investigators based on current data recommend mutations carriers consider risk reduction salpingoopherctomy (RRSO) beginning at age 45-50.
As research continues to evolve, physicians and researchers will gain a better understanding of how a RAD51D gene mutation will guide medical care. Because the information provided to patients will almost certainly change, those with a RAD51D gene mutation are encouraged to keep in touch with their medical providers in order to receive updates.
RAD51D testing in other family members
At this point in time, testing adult family members for a moderate risk gene mutation does NOT provide the same clarity or guidance that testing for a high risk gene mutation does. This is because moderate risk gene mutations should not be assumed to be the sole explanation for a particular family’s history of cancer. For example, a family could have additional undetected/ unknown genetic and/or non-genetic risk factors contributing to the development of cancer seen in family members. It is recommended that concerned family members discuss the issue of testing with their physicians. Given the current lack of data regarding RAD51D gene mutations, if an adult family member were to test negative for a familial RAD51D gene mutation, that individual may still be at increased risk for cancer depending upon the family history and possibility for other genes to be playing a role in that individual/ family. Cancer screening should be performed in accordance with the family history until further data is available.
Significance of pathogenic or likely pathogenic change in RAD51D
When pathogenic (harmful) or likely pathogenic (likely harmful) changes (mutations) are detected in RAD51D, this information is informative in 4 ways:
- Diagnostics: It might have contributed to a cancer developing and provides part of an explanation as to why someone develops cancer.
- Prevention: If identified in other family members, early screening or risk reductive surgical planning might be indicated and pursued. Evidenced based counseling framework related literature.
- Therapeutics: The RAD51D gene produces a protein in the body essential for repair of cells and if this function is altered, a cell may be unstable and develop into a cancer. Specific medications are being studied as part of clinical trials for people with an inability to appropriately repair their DNA due to changes in RAD51C and other DNA damage related genes. gov.
- Family Planning: Some individuals and families may decide to use genetic information for planning a family. It is important to know for RAD51D mutations carriers there is a 50% risk for an offspring to also inherit a damaging change.
Variant of Uncertain Significance (VUSs) in the RAD51D gene
In order for a change in a gene to be determined as pathogenic or likely pathogenic significant evidence or burden of proof is needed given the importance of decisions and recommendations to be made, therefore variants of uncertain significance which have not met this burden of proof should not guide recommendations.
Data Repositories for RAD51D Variants
The federal government is invested in learning more about variants of uncertain significance and tracking these variants in a central source called ClinVar. However, significant expertise and curation is required before variants are deposited in this central source. PROMPT is dedicated to generating quality data.
The consequences of misclassification can be significant and costly when individuals make life impacting decisions. Recently, the PROMPT study team illustrated in work spearheaded by Balamana et al. how different variants may be classified and the potential consequences of mis-classification based on the 4 main uses of this information by individuals and providers.
More information on the RAD51D gene:
- Gene Information: OMIM: 602954, Orphanet, DECIPHER
- Where to send testing: GeneTests
- Catalogue of mutations: ClinVar
- Registry information: Genetic Testing Registry
- Loveday C, Turnbull C, Ramsay E, et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet 2011;43:879–882.
- Song H, Dicks E, Ramus SJ, et al. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J Clin Oncol 2015;33:2901–2907.
- Tung N, Domchek SM, Stadler Z, Nathanson KL, Couch F, Garber JE, et al. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol. 2016;13(9):581-8. doi: 10.1038/nrclinonc.2016.90. PubMed PMID: 27296296.
- Pritchard CC, Mateo J, Walsh MF, et al: Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 375:443-53, 2016
- Walsh MF, Nathanson KL, Couch FJ, Offit K. Adv Exp Med Biol. 2016;882:1-32. Genomic Biomarkers for Breast Cancer Risk. doi: 10.1007/978-3-319-22909-6