BROVCA3; FANCO; R51H3; RAD51L2
The RAD51C gene is associated with an increased risk for autosomal dominant ovarian cancer and possibly breast cancer in individuals who carry a single pathogenic RAD51C variant (PMID: 20400964, 22451500, 22725699, 21616938). Additionally, the RAD51C gene has preliminary evidence supporting a correlation with autosomal recessive Fanconi anemia (PMID: 20400963).
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The RAD51C 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 RAD51C protein interacts with other RAD51 proteins and is involved in Holliday junction resolution. Loss of RAD51C function due to pathogenic variants causes defective DNA repair, leading to accumulation of DNA damage, thereby increasing the risk of tumor formation.
MedGen UID: 462009
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.
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.
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%.
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
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.
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