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RAD51D

Alias

BROVCA4; R51H3; RAD51L3; TRAD

Associated disorders

The RAD51D gene is associated with an increased risk for autosomal dominant ovarian cancer and possibly breast cancer (PMID: 21822267, 25445424).

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RAD51D

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Invitae tests that include this gene:

The RAD51D protein is part of the multi-component BCDX2 complex that includes several other members of the RAD51 family, such as RAD51B, RAD51C, and XRCC2. This complex binds to single-stranded DNA and is involved in the homologous recombinational repair of double-stranded DNA breaks arising during DNA replication or caused by DNA-damaging agents. RAD51D has also been reported to play a role in telomere maintenance (PMID: 15109494). Loss of RAD51D function due to mutation will have a deleterious effect on preserving genomic integrity, and is therefore expected to contribute to the onset of cancer (PMID: 23149936).

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 7-14% (PMID: 26720728, 23372765, 21822267, 26261251, 22652533, 26718727, 26689913, 27296296).

There is also preliminary evidence of an association between RAD51D and breast cancer (PMID: 21822267, 23372765, 25445424) and prostate cancer (PMID: 27433846, 22652533). Therefore, RAD51D is available as a preliminary-evidence gene on Invitae’s Breast Cancer Panel and Prostate Cancer Panel. 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). Accessed January 2017). 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.

Inheritance
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).

Management
The National Comprehensive Cancer Network® (NCCN®) recommends consideration of prophylactic salpingo-oophorectomy (surgical removal of the ovaries and fallopian tubes) for women with a pathogenic variant in RAD51D after childbearing is complete. The current evidence is insufficient to make a firm recommendation as to the optimal age for this procedure. However, based on the current, limited evidence, a discussion about surgery should be held around 45-50 years of age or earlier based on a specific family history of early-onset ovarian cancer ( NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2017). Women electing to defer prophylactic oophorectomy can consider screening for serum CA-125 and transvaginal ultrasound; however, data do not support such screening and it should not be a substitute for preventive surgery ( National Comprehensive Cancer Network®. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2017).

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 ( NCCN. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2017).

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 recommended screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Review date January 2017

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 in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

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