What are the implications and recommended management for an individual with the RAD50 (DNA repair protein) C.991A>G (p.K331E) mutation?

RAD50 C.991A>G (p.K331E) Mutation: Clinical Implications and Management

Immediate Clinical Significance

This RAD50 variant requires genetic counseling and consideration for cancer surveillance protocols, as RAD50 is a critical DNA repair gene within the MRN complex (MRE11/RAD50/NBN), and pathogenic variants confer increased cancer risk and DNA repair deficiency. 1, 2

Understanding RAD50 Function and Disease Association

RAD50 is essential for DNA double-strand break repair and functions as part of the MRN complex that activates homologous recombination repair and non-homologous end joining. 2, 3 The protein also maintains telomeres and stabilizes replication forks. 2

Known Pathogenic RAD50 Variants

• Biallelic loss-of-function RAD50 mutations cause an NBS-like disorder characterized by facial dysmorphisms, microcephaly, skeletal abnormalities, short stature, chromosomal instability, and defective ATM-dependent signaling. 2
• The single previously reported case with homozygous RAD50 loss-of-function showed abnormal radioresistant DNA synthesis and markedly reduced radiation-induced ATM signaling. 2
• Heterozygous carriers of pathogenic variants in DNA repair genes including RAD50 have been identified in cancer predisposition studies, though specific penetrance data for RAD50 remains limited. 1

Variant Classification Considerations

The c.991A>G (p.K331E) variant requires functional assessment to determine pathogenicity:

• Functional testing should evaluate whether this variant causes aberrant splicing, protein truncation, or loss of RAD50 function using patient-derived fibroblasts if available. 2
• Key functional assays include radioresistant DNA synthesis testing and assessment of radiation-induced ATM signaling. 2
• Protein expression studies via immunoblotting can determine if the variant leads to reduced RAD50 protein levels. 2

Cancer Risk Assessment

Established Associations with DNA Repair Gene Mutations

Germline mutations in homologous recombination repair genes (including RAD50) occur in 11.8% of men with metastatic prostate cancer and 6% of those with high-risk localized disease. 1

• In ovarian cancer, DNA repair gene mutations predict response to platinum-based chemotherapy and PARP inhibitors. 1
• Patients with DNA repair deficiencies show increased sensitivity to platinum agents and PARP inhibitors through synthetic lethality mechanisms. 1
• RAD50 is specifically mentioned alongside BRCA1/2, ATM, PALB2, and other DNA repair genes in cancer predisposition panels. 1

Cancer Surveillance Recommendations

If this variant is determined to be pathogenic or likely pathogenic, implement the following surveillance:

• Annual complete blood count to monitor for hematologic malignancies, as DNA repair disorders carry 40% risk of malignancy before age 20 in related syndromes. 1
• Annual physical examination with attention to lymphadenopathy and organomegaly. 1
• Head and neck cancer screening starting in adolescence with biannual dental examinations and annual otolaryngology evaluation, given the association of DNA repair disorders with squamous cell carcinomas. 1
• Consideration for enhanced breast and ovarian cancer surveillance in female carriers, as heterozygous carriers of DNA repair gene mutations have increased adult-onset cancer risk. 1
• Prostate cancer screening in male carriers starting at age 40-45, given the 11.8% prevalence of DNA repair mutations in metastatic prostate cancer. 1

Critical Management Considerations

Radiation Sensitivity

Patients with pathogenic RAD50 variants demonstrate increased sensitivity to ionizing radiation and require modified treatment protocols. 1, 2

• Limit diagnostic X-ray exposure to clinically essential situations only. 1
• If cancer develops, treatment regimens must be adjusted to account for increased risk of treatment-related toxicity. 1
• Coordinate care with centers experienced in managing DNA repair disorders. 1

Therapeutic Implications if Cancer Develops

DNA repair gene mutations predict response to specific cancer therapies:

• PARP inhibitors (olaparib, rucaparib) show efficacy in tumors with homologous recombination deficiency, with olaparib demonstrating improved radiographic PFS (HR 0.34) and OS (HR 0.69) in BRCA1/2/ATM-mutated metastatic prostate cancer. 1
• Platinum-based chemotherapy shows enhanced response in DNA repair-deficient tumors, with 100% complete/partial response rate in BRCA-mutated ovarian cancers versus 85% in wild-type. 1
• Standard chemotherapy dosing may require reduction due to increased toxicity risk. 1

Genetic Counseling Requirements

Refer immediately to genetic counseling for:

• Confirmation of variant pathogenicity through functional studies or segregation analysis. 2
• Family cascade testing if variant is pathogenic. 1
• Discussion of reproductive implications, as biallelic RAD50 mutations cause severe childhood-onset disease. 2
• Assessment of family cancer history for patterns suggesting hereditary cancer syndrome. 1

Monitoring for DNA Repair Deficiency

If variant is pathogenic, monitor for signs of DNA repair dysfunction:

• Baseline and periodic complete metabolic profile including lactate dehydrogenase. 1
• Evaluation by immunology for potential immunodeficiency, as related DNA repair disorders show IgA deficiency and reduced CD3+/CD4+ T cells. 1
• Pulmonary function testing if recurrent infections develop. 1
• Growth and developmental monitoring in pediatric patients. 1

Pitfalls to Avoid

• Do not assume benign status without functional validation, as novel RAD50 variants may cause aberrant splicing not predicted by sequence analysis alone. 2
• Do not use standard radiation therapy protocols if variant is pathogenic without consultation with radiation oncology experienced in DNA repair disorders. 1
• Do not delay genetic counseling pending functional studies; initiate referral immediately for family planning and cascade testing considerations. 1
• Do not overlook carrier status implications for family members, as even heterozygous carriers may have increased cancer risk. 1