RAD50

Chr 5AR

RAD50 double strand break repair protein

Also known as: NBSLD, RAD502, hRad50

NCBI Gene: 10111ENSG00000113522UniProt: Q92878

The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Rad50, a protein involved in DNA double-strand break repair. This protein forms a complex with MRE11 and NBS1. The protein complex binds to DNA and displays numerous enzymatic activities that are required for nonhomologous joining of DNA ends. This protein, cooperating with its partners, is important for DNA double-strand break repair, cell cycle checkpoint activation, telomere maintenance, and meiotic recombination. Knockout studies of the mouse homolog suggest this gene is essential for cell growth and viability. Mutations in this gene are the cause of Nijmegen breakage syndrome-like disorder.[provided by RefSeq, Apr 2010]

Primary Disease Associations & Inheritance

Nijmegen breakage syndrome-like disorderMIM #613078
AR
591
ClinVar variants
31
Pathogenic / LP
0.00
pLI score
5
Active trials
Clinical Summary— RAD50
🧬
Gene-Disease Validity (ClinGen)
hereditary breast carcinoma · ADRefuted

Refuted — evidence has disproved this relationship

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
31 Pathogenic / Likely Pathogenic· 414 VUS of 591 total submissions
💊
Clinical Trials
5 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.87LOEUF
pLI 0.000
Z-score 2.48
OE 0.70 (0.56–0.87)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.25Z-score
OE missense 0.86 (0.81–0.93)
587 obs / 678.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.70 (0.56–0.87)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.81–0.93)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.07
0≤1.21.6
LoF obs/exp: 54 / 77.6Missense obs/exp: 587 / 678.6Syn Z: -0.86

ClinVar Variant Classifications

591 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic14
VUS414
Likely Benign142
Benign1
Conflicting3
17
Pathogenic
14
Likely Pathogenic
414
VUS
142
Likely Benign
1
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
0
5
0
17
Likely Pathogenic
10
0
4
0
14
VUS
6
383
23
2
414
Likely Benign
0
3
31
108
142
Benign
0
0
1
0
1
Conflicting
—3
Total2838664110591

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

RAD50 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

RAD50-related Nijmegen breakage syndrome-like disorder

limited
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Nijmegen breakage syndrome-like disorder

MIM #613078

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — RAD50
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer.
Huang RX et al.·Signal Transduct Target Ther
2020Review
Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls.
Lilyquist J et al.·Gynecol Oncol
2017Cohort
Hereditary Ovarian Carcinoma: Cancer Pathogenesis Looking beyond BRCA1 and BRCA2.
Samuel D et al.·Cells
2022Review
Germline pathogenic variants in the MRE11, RAD50, and NBN (MRN) genes in cancer predisposition: A systematic review and meta-analysis.
Stastna B et al.·Int J Cancer
2024Meta-analysis
Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma.
Philip PA et al.·Clin Cancer Res
2022Cohort
A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants.
Ji J et al.·Cold Spring Harb Mol Case Stud
2019
MRE11 UFMylation promotes ATM activation.
Wang Z et al.·Nucleic Acids Res
2019
NBS1 facilitates preribosomal RNA biogenesis.
Luo M et al.·Proc Natl Acad Sci U S A
2025
Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.
Walsh T et al.·Proc Natl Acad Sci U S A
2011
Enhancement of glycolysis-dependent DNA repair regulated by FOXO1 knockdown via PFKFB3 attenuates hyperglycemia-induced endothelial oxidative stress injury.
Sun D et al.·Redox Biol
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Novel RAD50 variants lead to Nijmegen Breakage Syndrome-like disorder and unplanned recombinant human growth hormone treatment response.
Gong Y et al.·Front Endocrinol (Lausanne)
2026🔓 Open Access
Expanding the mutational spectrum of RAD50: a case report of Nijmegen breakage syndrome-like disorder in a Chinese child.
Sun H et al.·Gene
2026Case report
Pathogenic Germline PALB2 and RAD50 Variants in Patients With Relapsed Ewing Sarcoma.
Mack M et al.·Pediatr Blood Cancer
2026Cohort
Mutual, spatially limited control of meiotic DNA break formation by Mre11-Rad50-Nbs1 DNA repair complex and Tel1 (ATM) protein kinase.
Hyppa RW et al.·Nucleic Acids Res
2025🔓 Open Access
The bacterial MRE11-RAD50 and DNA2-WRN homologs process replication forks at distinct and separate loci on the chromosome.
Spolek RL et al.·FEBS Lett
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Polycythemia VeraEssential ThrombocythaemiaMyelofibrosis

Prevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History

NOT YET RECRUITING
NCT06923670Phase NAFondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2025-05-21
NGS testingNGS analysis for mutations in genes involved in familial predisposition to hematological malignancies
Gastric CancerGastroEsophageal Cancer

Study of SBRT/Olaparib Followed by Pembrolizumab/Olaparib in Gastric Cancers

ACTIVE NOT RECRUITING
NCT05379972Phase PHASE2University of Colorado, DenverStarted 2023-01-12
PembrolizumabOlaparibStereotactic Body Radiation Therapy
Advanced Solid TumorsEwing SarcomaHepatocellular Carcinoma (HCC)

A Phase 1/1B Study of ST-01156, a Small Molecule RBM39 Degrader, in Patients With Advanced Solid Malignancies

RECRUITING
NCT07197554Phase PHASE1SEED Therapeutics, Inc.Started 2025-12-01
ST-01156
Triple Negative Breast CancerBreast Cancer

Serial Circulating Tumor DNA (ctDNA) Monitoring During Adjuvant Capecitabine in Early Triple-negative Breast Cancer

RECRUITING
NCT04768426Phase PHASE2Stanford UniversityStarted 2021-02-03
Capecitabine
Metastatic Pancreatic Ductal AdenocarcinomaHomologous Recombination Deficiency (HRD)

A Study of Pembrolizumab and Olaparib for People With Metastatic Pancreatic Ductal Adenocarcinoma and Homologous Recombination Deficiency or Exceptional Treatment Response to Platinum-Based Therapy

ACTIVE NOT RECRUITING
NCT04666740Phase PHASE2Memorial Sloan Kettering Cancer CenterStarted 2020-12-18
PembrolizumabOlaparib

External Resources

Links to major genomics databases and tools