RAD50

RAD50 double strand break repair protein, the group of BRCA1 C complex|MRN complex

Basic information

Region (hg38): 5:132556018-132646349

Links

ENSG00000113522 ∙ NCBI:10111 ∙ OMIM:604040 ∙ HGNC:9816 ∙ Uniprot:Q92878 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Nijmegen breakage syndrome-like disorder (Limited), mode of inheritance: AR
• Nijmegen breakage syndrome-like disorder (Limited), mode of inheritance: AR
• Nijmegen breakage syndrome-like disorder (Strong), mode of inheritance: AR
• hereditary breast carcinoma (Refuted Evidence), mode of inheritance: AD
• familial ovarian cancer (Refuted Evidence), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Breast cancer, susceptibility to; Nijmegen breakage syndrome-like disorder	AD/AR	Audiologic/Otolaryngologic; Cardiovascular; Oncologic	In Breast cancer, susceptibility to, awareness may allow surveillance, preventive measures, and early diagnosis and treatment of disease; Nijmegen breakage syndrome-like disorder has been described as involving sensorineural hearing loss, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; An individual with Nijmegen breakage syndrome-like disorder has been described with arrhythmias, and awareness may allow early diagnosis and management of cardiac sequelae	Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic	14684699; 16474176; 1887849; 19092773; 19409520; 20571869; 21356067; 21799032; 22006311; 22048815; 22476849; 24549055; 24894818; 32212377

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RAD50 gene.

• Hereditary cancer-predisposing syndrome (3965 variants)
• Nijmegen breakage syndrome-like disorder (316 variants)
• not provided (225 variants)
• not specified (103 variants)
• Familial cancer of breast (30 variants)
• Hereditary breast ovarian cancer syndrome (20 variants)
• RAD50-related condition (19 variants)
• Ovarian cancer (10 variants)
• Inborn genetic diseases (7 variants)
• Breast and/or ovarian cancer (5 variants)
• Premature ovarian insufficiency (2 variants)
• Nijmegen breakage syndrome-like disorder;Breast cancer, susceptibility to (2 variants)
• Breast carcinoma (2 variants)
• Hereditary cancer-predisposing syndrome;Nijmegen breakage syndrome-like disorder (1 variants)
• Hepatocellular carcinoma (1 variants)
• See cases (1 variants)
• Neuroepithelial tumor, PATZ1 fusion-positive (1 variants)
• Nijmegen breakage syndrome-like disorder;Breast-ovarian cancer, familial, susceptibility to, 1 (1 variants)
• Malignant tumor of prostate (1 variants)
• Malignant tumor of breast (1 variants)
• Neoplasm of the skin (1 variants)
• Lung sarcomatoid carcinoma (1 variants)
• Myoepithelial tumor (1 variants)
• Familial cancer of breast;Nijmegen breakage syndrome-like disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RAD50 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			10	779	3	792
missense		1	2027	9	1	2038
nonsense	98	34	8			140
start loss		3	3			6
frameshift	179	39	15			233
inframe indel			34	1		35
splice donor/acceptor (+/-2bp)	3	72	5	1	1	82
splice region		9	100	108	11	228
non coding			35	332	54	421
Total	280	149	2137	1122	59

Highest pathogenic variant AF is 0.000140

Variants in RAD50

This is a list of pathogenic ClinVar variants found in the RAD50 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
5-132556665-C-T			Benign (Apr 09, 2019)
5-132556973-G-A			not provided (-)
5-132557041-C-A			not provided (-)
5-132557287-G-G		not specified	Benign (Oct 23, 2013)
5-132557322-A-G		Hereditary cancer-predisposing syndrome	Uncertain significance (Nov 14, 2022)
5-132557324-C-T		Hereditary cancer-predisposing syndrome	Uncertain significance (Mar 05, 2018)
5-132557325-A-G		Hereditary cancer-predisposing syndrome	Likely pathogenic (Nov 12, 2021)
5-132557327-G-A		Hereditary cancer-predisposing syndrome • Nijmegen breakage syndrome-like disorder	Pathogenic/Likely pathogenic (Jan 15, 2024)
5-132557328-T-A		Hereditary cancer-predisposing syndrome	Uncertain significance (Dec 31, 2023)
5-132557328-T-C		Hereditary cancer-predisposing syndrome	Uncertain significance (Feb 03, 2023)
5-132557328-T-G		Hereditary cancer-predisposing syndrome	Uncertain significance (Jun 22, 2022)
5-132557329-C-T		Hereditary cancer-predisposing syndrome	Conflicting classifications of pathogenicity (Aug 27, 2018)
5-132557330-C-T		Hereditary cancer-predisposing syndrome	Likely benign (Jul 12, 2022)
5-132557331-C-T		Hereditary cancer-predisposing syndrome	Uncertain significance (Dec 10, 2023)
5-132557332-G-A		Hereditary cancer-predisposing syndrome	Uncertain significance (Apr 08, 2021)
5-132557332-G-T		Hereditary cancer-predisposing syndrome	Uncertain significance (Apr 25, 2023)
5-132557333-G-A		Hereditary cancer-predisposing syndrome	Likely benign (Dec 29, 2023)
5-132557333-G-C		Hereditary cancer-predisposing syndrome	Likely benign (Oct 25, 2022)
5-132557334-A-G		Hereditary cancer-predisposing syndrome	Uncertain significance (Sep 10, 2023)
5-132557336-C-A		Hereditary cancer-predisposing syndrome	Likely benign (Sep 24, 2023)
5-132557336-C-T		Hereditary cancer-predisposing syndrome	Likely benign (Jan 29, 2020)
5-132557336-CG-TT		Hereditary cancer-predisposing syndrome	Likely pathogenic (Feb 14, 2020)
5-132557337-G-A		Hereditary cancer-predisposing syndrome	Uncertain significance (Nov 30, 2023)
5-132557337-GA-G		Hereditary cancer-predisposing syndrome	Pathogenic (Mar 22, 2022)
5-132557338-A-G		Hereditary cancer-predisposing syndrome	Uncertain significance (Mar 20, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RAD50	protein_coding	protein_coding	ENST00000265335	25	88603

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.44e-27	0.716	125214	0	534	125748	0.00213

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.25	587	679	0.865	0.0000357	8776
Missense in Polyphen		163	185.44	0.87899		2257
Synonymous	-0.859	239	223	1.07	0.0000104	2246
Loss of Function	2.48	54	77.6	0.696	0.00000440	928

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00406	0.00398
Ashkenazi Jewish	0.000605	0.000595
East Asian	0.00253	0.00250
Finnish	0.00554	0.00551
European (Non-Finnish)	0.00161	0.00158
Middle Eastern	0.00253	0.00250
South Asian	0.00215	0.00213
Other	0.00278	0.00277

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis. The complex possesses single-strand endonuclease activity and double-strand- specific 3'-5' exonuclease activity, which are provided by MRE11. RAD50 may be required to bind DNA ends and hold them in close proximity. This could facilitate searches for short or long regions of sequence homology in the recombining DNA templates, and may also stimulate the activity of DNA ligases and/or restrict the nuclease activity of MRE11 to prevent nucleolytic degradation past a given point (PubMed:11741547, PubMed:9590181, PubMed:9705271, PubMed:9651580). The complex may also be required for DNA damage signaling via activation of the ATM kinase (PubMed:15064416). In telomeres the MRN complex may modulate t-loop formation (PubMed:10888888). {ECO:0000269|PubMed:10888888, ECO:0000269|PubMed:11741547, ECO:0000269|PubMed:15064416, ECO:0000269|PubMed:9590181, ECO:0000269|PubMed:9651580, ECO:0000269|PubMed:9705271}.
• Disease: DISEASE: Nijmegen breakage syndrome-like disorder (NBSLD) [MIM:613078]: A disorder similar to Nijmegen breakage syndrome and characterized by chromosomal instability, radiation sensitivity, microcephaly, growth retardation, short stature and bird-like face. Immunodeficiency is absent. {ECO:0000269|PubMed:19409520}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Homologous recombination - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Non-homologous end-joining - Homo sapiens (human);miRNA Regulation of DNA Damage Response;Homologous recombination;DDX1 as a regulatory component of the Drosha microprocessor;ATM Signaling Network in Development and Disease;Non-homologous end joining;DNA Damage Response;HDR through Single Strand Annealing (SSA);HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA);HDR through MMEJ (alt-NHEJ);DNA Repair;Gene expression (Transcription);Nonhomologous End-Joining (NHEJ);DNA Double-Strand Break Repair;role of brca1 brca2 and atr in cancer susceptibility;Generic Transcription Pathway;DNA Damage/Telomere Stress Induced Senescence;Cellular Senescence;Homology Directed Repair;Cellular responses to stress;RNA Polymerase II Transcription;G2/M DNA damage checkpoint;G2/M Checkpoints;Cell Cycle Checkpoints;Cellular responses to external stimuli;Fanconi anemia pathway;Regulation of TP53 Activity through Phosphorylation;Regulation of TP53 Activity;Transcriptional Regulation by TP53;Sensing of DNA Double Strand Breaks;Cell Cycle;Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks;DNA Double Strand Break Response;Regulation of Telomerase;BARD1 signaling events;Processing of DNA double-strand break ends;ATM pathway;Presynaptic phase of homologous DNA pairing and strand exchange;Homologous DNA Pairing and Strand Exchange;Resolution of D-loop Structures through Holliday Junction Intermediates;Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA);Resolution of D-Loop Structures;HDR through Homologous Recombination (HRR) (Consensus)

Recessive Scores

• pRec: 0.586

Intolerance Scores

• loftool: 0.987
• rvis_EVS: -0.5
• rvis_percentile_EVS: 21.84

Haploinsufficiency Scores

• pHI: 0.754
• hipred: N
• hipred_score: 0.492
• ghis: 0.611

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.958

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Rad50
• Phenotype: cellular phenotype; endocrine/exocrine gland phenotype; neoplasm; growth/size/body region phenotype; hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); reproductive system phenotype; digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; liver/biliary system phenotype; embryo phenotype; pigmentation phenotype

Gene ontology

• Biological process: regulation of mitotic recombination;telomere maintenance via recombination;telomere maintenance;double-strand break repair via homologous recombination;DNA double-strand break processing;DNA replication;DNA repair;double-strand break repair;double-strand break repair via nonhomologous end joining;DNA recombination;cellular response to DNA damage stimulus;telomere maintenance via telomerase;reciprocal meiotic recombination;viral process;telomere capping;telomeric 3' overhang formation;positive regulation of protein autophosphorylation;positive regulation of telomere maintenance;DNA duplex unwinding;positive regulation of kinase activity;nucleoside monophosphate phosphorylation;chromosome organization involved in meiotic cell cycle;nucleic acid phosphodiester bond hydrolysis;negative regulation of telomere capping
• Cellular component: nuclear chromosome, telomeric region;nuclear chromatin;condensed nuclear chromosome;nucleoplasm;membrane;Mre11 complex;site of double-strand break
• Molecular function: single-stranded DNA endodeoxyribonuclease activity;DNA binding;double-stranded telomeric DNA binding;ATP-dependent DNA helicase activity;adenylate kinase activity;protein binding;ATP binding;3'-5' exonuclease activity;protein binding, bridging;single-stranded telomeric DNA binding;metal ion binding;G-quadruplex DNA binding