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RAD51C

Alias

BROVCA3; FANCO; R51H3; RAD51L2

Associated disorders

The RAD51C gene is associated with autosomal dominant susceptibility to ovarian cancer and possibly breast cancer (PMID: 20400964, 22451500, 22725699, 21616938).

The RAD51C protein is part of the multi-component BCDX2 complex that includes several other members of the RAD51 family, such as RAD51B, RAD51D, 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. Loss of RAD51C 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).

RAD51C heterozygote
MedGen UID: 462009

Clinical condition
Women who are carriers of a single pathogenic RAD51C variant have an increased risk of ovarian cancer. Studies suggest this risk is approximately 5.2-9% (PMID: 26720728, 20400964, 21616938, 22538716, 22451500, 22725699, 26261251, 26689913, 25470109). There is also preliminary evidence of an association with RAD51C and breast cancer, and RAD51C is therefore available as a preliminary evidence gene on Invitae’s Breast Cancer panel (PMID: 22725699, 23300655, 25470109, 22451500, 25470109, 26740214). 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 limited evidence genes. An individual with a RAD51C pathogenic variant will not necessarily develop cancer in their lifetime, however, their risk of cancer is increased over that of the general population.

Gene information
The RAD51C gene is essential for the homologous recombination pathway of DNA repair, also known as the Fanconi anemia pathway. It is involved in the homologous recombination repair pathway of double-stranded DNA breaks that arise during DNA replication or that are induced by DNA-damaging agents (UniProtKB – O43502 (RA51C_HUMAN) Accessed January 2017). If there is a pathogenic variant in this gene that prevents it from normally functioning, there may be an increased risk to develop certain types of cancers.

Inheritance
Hereditary predisposition to cancer due to pathogenic variants in the RAD51C 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).

Individuals with a single pathogenic variant in RAD51C are also carriers of autosomal recessive Fanconi anemia (PMID: 20400963). Fanconi anemia is characterized by bone marrow failure with variable additional anomalies that often include short stature, abnormal skin pigmentation, abnormal thumbs, malformations of the skeletal and central nervous systems, and developmental delay (PMID: 8986277, 20417588). Risks for leukemia and early-onset solid tumors are significantly elevated with this disorder (PMID: 12393516, 12393424, 20507306). For there to be a risk of Fanconi anemia in offspring, both parents would each have to have a pathogenic variant in RAD51C; in this case, the risk of having an affected child is 25%.

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 RAD51C 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 base, 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 ( National Comprehensive Cancer Network®. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2017). Additionally, NCCN® recommends genetic counseling in regards to recurrence risks.

The current NCCN® guidelines do not recommend additional breast cancer screening for individuals with a single pathogenic RAD51C 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 RAD51C is still emerging, knowing if a pathogenic 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 RAD51C 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
RAD51C NM_058216.2