Associated disorders

The RAD51D gene is associated with an increased risk for autosomal dominant ovarian cancer and possibly breast cancer in individuals who carry a single pathogenic variant.

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The RAD51D gene encodes a protein essential for the homologous recombination repair pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents. The RAD51D protein interacts with other RAD51 proteins and is involved in Holliday junction resolution. Loss of RAD51D function due to pathogenic variants causes defective DNA repair, leading to accumulation of DNA damage, thereby increasing the risk of tumor formation.

RAD51D heterozygote
MedGen UID: 452094

Clinical condition
Women who are carriers of a single pathogenic RAD51D variant have an increased risk of ovarian cancer. Studies suggest this risk is 7-12% (PMID: 26720728, 23372765, 21822267, 26261251, 22652533, 26718727, 26689913). There is also preliminary evidence of an association between RAD51D and breast cancer, and RAD51D is therefore available as a preliminary-evidence gene on Invitae’s Breast Cancer Panel (PMID: 21822267, 23372765, 25445424). Preliminary-evidence genes are selected from an extensive review of the literature and expert recommendations, but the association between the gene and the specific condition has not been completely established. This uncertainty may be resolved as new information becomes available, and therefore clinicians may continue to order these preliminary-evidence genes. Individuals with a pathogenic variant in RAD51D will not necessarily develop cancer in their lifetime, however, their risk of cancer is increased over that of the general population.

Gene information
The RAD51D gene is essential to DNA repair. It is involved in the homologous recombination repair pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents (UniProtKB – O75771 (RA51D_HUMAN); http://www.uniprot.org/uniprot/O75771. Accessed September 2015). If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain types of cancers may be increased.

Hereditary predisposition to cancer due to a single pathogenic variant in the RAD51D gene has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. With this result, it is now possible to identify at-risk relatives who can pursue testing for this specific familial variant. Many cases are inherited from a parent, but some cases can occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it).

The National Comprehensive Cancer Network (NCCN) recommends consideration of prophylactic salpingo-oophorectomy (surgical removal of the ovaries and fallopian tubes) after childbearing is complete for women with a pathogenic variant in RAD51D ( National Comprehensive Cancer Network. Breast and Ovarian Management Based on Genetic Test Results. Version 2.2016). The current NCCN guidelines do not recommend additional breast cancer screening for individuals with a single pathogenic RAD51D variant beyond what is recommended for the general population. However, they caution that cancer screening should ultimately be guided by personal and family history ( National Comprehensive Cancer Network. Breast and Ovarian Management Based on Genetic Test Results. Version 2.2016).

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Even though data regarding pathogenic variants in RAD51D is still emerging, knowing if such a variant is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding RAD51D are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to diligently follow standard screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Review Date: August 2016

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
RAD51D NM_002878.3