The RAD51C gene is classified as a tumor suppressor, meaning its normal function is to help prevent the uncontrolled cell growth that leads to cancer. A pathogenic variant, or mutation, in this gene is associated with an elevated, inherited risk for certain cancers, primarily ovarian and breast cancer. When a person inherits a non-working copy of RAD51C, this protective mechanism is compromised, increasing the likelihood of developing these specific cancers over a lifetime. Understanding the function of this gene, the specific risks involved, and the available medical management options is important for individuals who test positive for this mutation.
The Function of the RAD51C Gene
The RAD51C gene, located on chromosome 17q22, provides instructions for making a protein involved in DNA repair. This protein is a component of a larger complex responsible for homologous recombination (HR), the cell’s primary method for repairing double-strand breaks (DSBs) where both strands of the DNA helix are severed.
The RAD51C protein works with other related proteins, called paralogs, forming complexes that manage different stages of the HR process. When a pathogenic mutation occurs, the protein cannot be made or function properly within these complexes. This failure in the repair pathway allows errors to accumulate in the DNA, causing genomic instability, which is a hallmark of cancer development. The cell thus becomes more susceptible to uncontrolled proliferation and tumor formation.
Cancer Risks Linked to RAD51C Mutation
A pathogenic RAD51C mutation increases the lifetime risk for developing ovarian and breast cancer. The risk for ovarian cancer is the most pronounced, with lifetime estimates for carriers reaching approximately 9% to 15% by age 80, compared to less than 1% in the general population. The average age of ovarian cancer diagnosis in RAD51C carriers is often later than in BRCA1 carriers, frequently around age 60 to 62.
The risk for female breast cancer is also elevated, ranging from 20% to 30% by age 80. Research suggests that breast cancers associated with this mutation are more frequently the aggressive Triple-Negative Breast Cancer (TNBC) subtype, which lacks estrogen, progesterone, and HER2 receptors. The cancer risks for men with a RAD51C mutation are not currently known to be elevated. Individuals who inherit two non-working copies of RAD51C (one from each parent) are at risk for the severe childhood blood disorder Fanconi Anemia (FA-O subtype), though this is extremely rare.
Hereditary Transmission and Genetic Screening
The cancer predisposition associated with a RAD51C mutation follows an Autosomal Dominant inheritance pattern, meaning a person only needs to inherit one mutated copy of the gene to have the elevated cancer risk. Each child of a carrier parent has a 50% chance of inheriting the pathogenic variant.
Genetic screening is recommended for individuals with a strong personal or family history of breast or ovarian cancer, particularly those diagnosed with ovarian cancer at any age or early-onset breast cancer. The screening involves a simple blood or saliva test to analyze the RAD51C gene sequence. Genetic counseling is essential to help individuals understand the implications of the test results, the specific cancer risks based on their family history, and the options available for risk management. Testing children is generally not recommended, as the cancer risks manifest in adulthood and interventions are not required before age 18.
Medical Management for Carriers
Medical management for women identified as RAD51C carriers focuses on enhanced surveillance and risk-reducing procedures. For ovarian cancer prevention, the most effective strategy is a risk-reducing salpingo-oophorectomy (RRSO), which involves the surgical removal of the ovaries and fallopian tubes. This procedure is generally considered between the ages of 45 and 50, or earlier if there is a family history of younger-onset ovarian cancer, to balance risk reduction with the effects of early menopause.
Routine ovarian cancer screening using transvaginal ultrasound and CA-125 blood tests is not proven effective for early detection and is not typically recommended for surveillance. For breast cancer surveillance, guidelines recommend annual screening starting at age 40, combining mammograms and breast magnetic resonance imaging (MRI). Risk-reducing mastectomy (RRM) is also an option based on individual risk factors and family history. Since RAD51C is a DNA repair gene, cancers that develop in carriers may be sensitive to targeted therapies, such as PARP inhibitors.