GeneBe

ATM

ATM serine/threonine kinase, the group of Armadillo like helical domain containing

Basic information

Region (hg38): 11:108222804-108369102

Previous symbols: [ "ATA", "ATDC", "ATC", "ATD" ]

Links

ENSG00000149311 ∙ NCBI:472 ∙ OMIM:607585 ∙ HGNC:795 ∙ Uniprot:Q13315 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

  • ataxia telangiectasia (Definitive), mode of inheritance: AR
  • sarcoma (Moderate), mode of inheritance: AD
  • ataxia telangiectasia (Strong), mode of inheritance: AR
  • ataxia telangiectasia (Definitive), mode of inheritance: AR
  • hereditary breast carcinoma (Definitive), mode of inheritance: AD
  • ataxia telangiectasia (Definitive), mode of inheritance: AR
  • ataxia telangiectasia (Supportive), mode of inheritance: AR
  • prostate cancer (Limited), mode of inheritance: AD
  • ataxia telangiectasia (Strong), mode of inheritance: AR
  • familial ovarian cancer (Limited), mode of inheritance: AD
  • hereditary nonpolyposis colon cancer (Moderate), mode of inheritance: AD
  • hereditary breast carcinoma (Definitive), mode of inheritance: AD
  • ataxia telangiectasia (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Breast cancer, susceptibility to; Ataxia-TelangiectasiaAD/ARAllergy/Immunology/Infectious; OncologicFor breast cancer, susceptibility to, awareness of the risk of malignancy may allow surveillance, preventive measures, and early diagnosis and treatment; In Ataxia-Telangiectasia, for infectious complications, prophylaxis and early and aggressive treatment of infections can be beneficial; Surveillance for malignancy can be beneficial; Precautions should be taken related to ionizing radiation and chemotherapeutic regimens (eg, related to dosage)Allergy/Immunology/Infectious; Neurologic; Oncologic; Ophthalmologic311128; 4515676; 4132004; 310962; 7124732; 3496017; 3785360; 3788973; 3574400; 2916583; 2136770; 2253179; 2005780; 1961222; 1304718; 1377828; 8365732; 7836845; 7792600; 8976369; 9054927; 9259193; 9054948; 9463314; 10571946; 10425038; 9887333; 10677309; 10980530; 11826028; 12226795; 12552559; 15942625; 16864838; 16832357; 19535770; 19440741; 20301790; 21429505; 23264026; 23612382; 23900766; 25186627; 25330149
Though the evidence is overall difficult to interpret, heterozygotes may be at increased risk of a number of types of malignancies

ClinVar

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

  • Ataxia-telangiectasia syndrome (1243 variants)
  • Familial cancer of breast (852 variants)
  • Hereditary cancer-predisposing syndrome (833 variants)
  • not provided (178 variants)
  • Gastric cancer (22 variants)
  • Familial cancer of breast;Ataxia-telangiectasia syndrome (16 variants)
  • ATM-related disorder (15 variants)
  • Malignant tumor of breast (14 variants)
  • Breast and/or ovarian cancer (13 variants)
  • Malignant tumor of urinary bladder (11 variants)
  • Ataxia-telangiectasia syndrome;Familial cancer of breast (7 variants)
  • Breast carcinoma (5 variants)
  • Abnormal central motor function (5 variants)
  • Hereditary breast ovarian cancer syndrome (5 variants)
  • not specified (4 variants)
  • Ataxia-telangiectasia syndrome;Breast cancer, susceptibility to (4 variants)
  • Breast cancer, susceptibility to (3 variants)
  • Breast cancer, susceptibility to;Ataxia-telangiectasia syndrome (3 variants)
  • Tip-toe gait (2 variants)
  • Endometrial carcinoma (2 variants)
  • Ataxia telangiectasi (2 variants)
  • Familial pancreatic carcinoma (2 variants)
  • Carcinoma of colon (2 variants)
  • Ataxia-telangiectasia syndrome;Malignant tumor of breast (2 variants)
  • T-cell prolymphocytic leukemia (2 variants)
  • Ataxia-telangiectasia syndrome;Hereditary cancer-predisposing syndrome (1 variants)
  • Ataxia-telangiectasia without immunodeficiency (1 variants)
  • Ataxia - telangiectasia variant (1 variants)
  • Ovarian carcinoma (1 variants)
  • Colorectal cancer (1 variants)
  • Malignant glioma (1 variants)
  • ATM-related cancer predisposition syndrome (1 variants)
  • Inherited breast cancer and ovarian cancer (1 variants)
  • Seizure (1 variants)
  • NICE approved PARP inhibitor treatment (1 variants)
  • Cerebellar ataxia (1 variants)
  • Cerebellar ataxia;Seizure (1 variants)
  • Mantle cell lymphoma (1 variants)
  • Breast neoplasm (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ATM 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
3
clinvar
29
clinvar
2452
clinvar
3
clinvar
 2487
missense
9
clinvar
59
clinvar
6839
clinvar
44
clinvar
17
clinvar
 6968
nonsense
562
clinvar
198
clinvar
9
clinvar
2
clinvar
 771
start loss
3
clinvar
3
clinvar
 6
frameshift
1324
clinvar
373
clinvar
8
clinvar
 1705
inframe indel
3
clinvar
7
clinvar
200
clinvar
1
clinvar
 211
splice donor/acceptor (+/-2bp)
65
clinvar
417
clinvar
16
clinvar
8
clinvar
3
clinvar
 509
splice region
4
39
360
410
9
 822
non coding
5
clinvar
22
clinvar
204
clinvar
1429
clinvar
152
clinvar
 1812
Total 1971 1082 7305 3936 175

Highest pathogenic variant AF is 0.000197

Variants in ATM

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

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

Position Type Phenotype Significance ClinVar
11-108222819-G-A Ataxia-telangiectasia syndrome Uncertain significance (Jan 13, 2018)879221
11-108222846-G-C not specified • Familial cancer of breast;Ataxia-telangiectasia syndrome Uncertain significance (Nov 18, 2021)434433
11-108222889-A-T Ataxia-telangiectasia syndrome Likely benign (Aug 15, 2019)302233
11-108222890-T-C not specified Uncertain significance (May 04, 2018)1336095
11-108222935-T-G not specified Uncertain significance (Mar 19, 2020)1337132
11-108222943-G-A Ataxia-telangiectasia syndrome Uncertain significance (Jun 14, 2016)302234
11-108222976-G-C not specified Uncertain significance (Feb 16, 2021)1337835
11-108222980-AC-A Ataxia-telangiectasia syndrome Uncertain significance (Jun 14, 2016)302235
11-108222988-C-G Ataxia-telangiectasia syndrome Uncertain significance (Jan 13, 2018)302236
11-108222995-T-A Ataxia-telangiectasia syndrome Uncertain significance (Jan 13, 2018)302237
11-108222999-T-A Ataxia-telangiectasia syndrome • not specified Uncertain significance (Dec 17, 2020)302238
11-108223031-G-A Ataxia-telangiectasia syndrome Uncertain significance (Jan 12, 2018)302239
11-108223043-A-C Ataxia-telangiectasia syndrome Uncertain significance (Apr 27, 2017)880418
11-108223046-G-A not specified Uncertain significance (Jun 14, 2021)1337970
11-108223070-T-C not specified Uncertain significance (Aug 14, 2019)1337318
11-108223090-A-G not specified Uncertain significance (Sep 28, 2020)1337752
11-108223106-G-A Ataxia-telangiectasia syndrome Benign (Jan 22, 2024)302240
11-108223106-GCG-AC Ataxia-telangiectasia syndrome Uncertain significance (Sep 18, 2017)553892
11-108223123-G-A Ataxia-telangiectasia syndrome • not specified Uncertain significance (Dec 03, 2021)302241
11-108223143-G-A Ataxia-telangiectasia syndrome Uncertain significance (Jan 13, 2018)302242
11-108223170-A-G not specified Likely benign (Aug 19, 2016)388798
11-108223174-T-G not specified Likely benign (May 04, 2016)379271
11-108223175-C-T not specified Likely benign (Sep 26, 2016)389599
11-108223183-A-G Uncertain significance (Oct 07, 2016)422472
11-108223183-A-AGT not specified Uncertain significance (Jan 04, 2017)234796

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
ATMprotein_codingprotein_codingENST00000278616 62146619
pLI Probability
LOF Intolerant 		pRec Probability
LOF Recessive 		Individuals with
no LOFs 		Individuals with
Homozygous LOFs 		Individuals with
Heterozygous LOFs 		Defined p
5.59e-471.0012538503631257480.00144
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense1.1014111.53e+30.9210.000077520140
Missense in Polyphen261364.090.716864832
Synonymous-0.8645555301.050.00002645525
Loss of Function4.821031710.6030.000009112183

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.002560.00256
Ashkenazi Jewish0.0006950.000695
East Asian0.001580.00147
Finnish0.0003710.000370
European (Non-Finnish)0.001720.00172
Middle Eastern0.001580.00147
South Asian0.001270.00124
Other0.001970.00196

dbNSFP

Source: dbNSFP

Function
FUNCTION: Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX at double strand breaks (DSBs), thereby regulating DNA damage response mechanism. Also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. After the introduction of DNA breaks by the RAG complex on one immunoglobulin allele, acts by mediating a repositioning of the second allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. Also involved in signal transduction and cell cycle control. May function as a tumor suppressor. Necessary for activation of ABL1 and SAPK. Phosphorylates DYRK2, CHEK2, p53/TP53, FANCD2, NFKBIA, BRCA1, CTIP, nibrin (NBN), TERF1, RAD9 and DCLRE1C. May play a role in vesicle and/or protein transport. Could play a role in T-cell development, gonad and neurological function. Plays a role in replication-dependent histone mRNA degradation. Binds DNA ends. Phosphorylation of DYRK2 in nucleus in response to genotoxic stress prevents its MDM2-mediated ubiquitination and subsequent proteasome degradation. Phosphorylates ATF2 which stimulates its function in DNA damage response. {ECO:0000269|PubMed:10973490, ECO:0000269|PubMed:12556884, ECO:0000269|PubMed:14871926, ECO:0000269|PubMed:15916964, ECO:0000269|PubMed:16086026, ECO:0000269|PubMed:16858402, ECO:0000269|PubMed:17923702, ECO:0000269|PubMed:19431188, ECO:0000269|PubMed:19965871}.;
Disease
DISEASE: Ataxia telangiectasia (AT) [MIM:208900]: A rare recessive disorder characterized by progressive cerebellar ataxia, dilation of the blood vessels in the conjunctiva and eyeballs, immunodeficiency, growth retardation and sexual immaturity. Patients have a strong predisposition to cancer; about 30% of patients develop tumors, particularly lymphomas and leukemias. Cells from affected individuals are highly sensitive to damage by ionizing radiation and resistant to inhibition of DNA synthesis following irradiation. {ECO:0000269|PubMed:10234507, ECO:0000269|PubMed:10425038, ECO:0000269|PubMed:10817650, ECO:0000269|PubMed:10873394, ECO:0000269|PubMed:19431188, ECO:0000269|PubMed:27664052, ECO:0000269|PubMed:7792600, ECO:0000269|PubMed:8589678, ECO:0000269|PubMed:8665503, ECO:0000269|PubMed:8698354, ECO:0000269|PubMed:8755918, ECO:0000269|PubMed:8789452, ECO:0000269|PubMed:8797579, ECO:0000269|PubMed:8808599, ECO:0000269|PubMed:8845835, ECO:0000269|PubMed:9043869, ECO:0000269|PubMed:9150358, ECO:0000269|PubMed:9443866, ECO:0000269|PubMed:9450874, ECO:0000269|PubMed:9463314, ECO:0000269|PubMed:9497252, ECO:0000269|PubMed:9521587, ECO:0000269|PubMed:9711876, ECO:0000269|PubMed:9792409, ECO:0000269|PubMed:9792410, ECO:0000269|PubMed:9872980, ECO:0000269|PubMed:9887333}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in ATM may contribute to T-cell acute lymphoblastic leukemia (TALL) and T-prolymphocytic leukemia (TPLL). TPLL is characterized by a high white blood cell count, with a predominance of prolymphocytes, marked splenomegaly, lymphadenopathy, skin lesions and serous effusion. The clinical course is highly aggressive, with poor response to chemotherapy and short survival time. TPLL occurs both in adults as a sporadic disease and in younger AT patients. {ECO:0000269|PubMed:9288106, ECO:0000269|PubMed:9334731, ECO:0000269|PubMed:9463314, ECO:0000269|PubMed:9488043, ECO:0000269|PubMed:9573030}.; DISEASE: Note=Defects in ATM may contribute to B-cell non-Hodgkin lymphomas (BNHL), including mantle cell lymphoma (MCL). {ECO:0000269|PubMed:10397742, ECO:0000269|PubMed:10706620, ECO:0000269|PubMed:9288106}.; DISEASE: Note=Defects in ATM may contribute to B-cell chronic lymphocytic leukemia (BCLL). BCLL is the commonest form of leukemia in the elderly. It is characterized by the accumulation of mature CD5+ B-lymphocytes, lymphadenopathy, immunodeficiency and bone marrow failure. {ECO:0000269|PubMed:10023947, ECO:0000269|PubMed:10397742, ECO:0000269|PubMed:9892178}.;
Pathway
Cell cycle - Homo sapiens (human);p53 signaling pathway - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Homologous recombination - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);Transcriptional misregulation in cancer - Homo sapiens (human);Apoptosis - Homo sapiens (human);NF-kappa B signaling pathway - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Metformin Pathway, Pharmacodynamic;Cell Cycle;miRNA Regulation of DNA Damage Response;miRNAs involved in DNA damage response;TP53 Network;Homologous recombination;Signaling Pathways in Glioblastoma;ATM Signaling Pathway;DDX1 as a regulatory component of the Drosha microprocessor;Ovarian Infertility Genes;Pathways Affected in Adenoid Cystic Carcinoma;Hematopoietic Stem Cell Gene Regulation by GABP alpha-beta Complex;TP53 Regulates Transcription of DNA Repair Genes;ATM Signaling Network in Development and Disease;DNA IR-Double Strand Breaks (DSBs) and cellular response via ATM;miRNA regulation of p53 pathway in prostate cancer;DNA IR-damage and cellular response via ATR;apoptotic signaling in response to dna damage;G1 to S cell cycle control;DNA Damage Response;DNA Damage Response (only ATM dependent);HDR through Single Strand Annealing (SSA);HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA);DNA Repair;Gene expression (Transcription);Nonhomologous End-Joining (NHEJ);DNA Double-Strand Break Repair;hypoxia and p53 in the cardiovascular system;role of brca1 brca2 and atr in cancer susceptibility;tumor suppressor arf inhibits ribosomal biogenesis;cdc25 and chk1 regulatory pathway in response to dna damage;cell cycle: g1/s check point;regulation of cell cycle progression by plk3;Generic Transcription Pathway;Regulation of HSF1-mediated heat shock response;DNA Damage/Telomere Stress Induced Senescence;Cellular Senescence;Homology Directed Repair;Cellular responses to stress;TP53 Regulates Transcription of Cell Death Genes;RNA Polymerase II Transcription;Autodegradation of the E3 ubiquitin ligase COP1;Stabilization of p53;p53-Dependent G1 DNA Damage Response;p53-Dependent G1/S DNA damage checkpoint;Ubiquitin Mediated Degradation of Phosphorylated Cdc25A;p53-Independent DNA Damage Response;p53-Independent G1/S DNA damage checkpoint;G1/S DNA Damage Checkpoints;G2/M DNA damage checkpoint;G2/M Checkpoints;Cell Cycle Checkpoints;TP53 Regulates Transcription of Genes Involved in Cytochrome C Release;cell cycle: g2/m checkpoint;TP53 Regulates Transcription of Caspase Activators and Caspases;Cellular responses to external stimuli;atm signaling pathway;TP53 Regulates Transcription of DNA Repair Genes;Fanconi anemia pathway;rb tumor suppressor/checkpoint signaling in response to dna damage;Regulation of TP53 Degradation;Regulation of TP53 Expression and Degradation;Cellular response to heat stress;Regulation of TP53 Activity through Phosphorylation;Regulation of TP53 Activity through Methylation;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;Canonical NF-kappaB pathway;Regulation of Telomerase;Validated transcriptional targets of deltaNp63 isoforms;BARD1 signaling events;Processing of DNA double-strand break ends;p38 MAPK signaling pathway;ATM pathway;E2F transcription factor network;p53 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
0.158

Intolerance Scores

loftool
0.782
rvis_EVS
1.53
rvis_percentile_EVS
95.51

Haploinsufficiency Scores

pHI
0.170
hipred
Y
hipred_score
0.747
ghis
0.531

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
S
essential_gene_gene_trap
gene_indispensability_pred
E
gene_indispensability_score
0.915

Gene Damage Prediction

AllRecessiveDominant
MendelianHighHighHigh
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh

Mouse Genome Informatics

Gene name
Atm
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); immune system phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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); reproductive system phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); neoplasm; endocrine/exocrine gland phenotype; cellular phenotype; homeostasis/metabolism phenotype; 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); growth/size/body region phenotype;

Gene ontology

Biological process
DNA damage checkpoint;telomere maintenance;DNA double-strand break processing;response to hypoxia;pre-B cell allelic exclusion;DNA replication;double-strand break repair via nonhomologous end joining;protein phosphorylation;cellular response to DNA damage stimulus;DNA damage induced protein phosphorylation;DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest;cell cycle arrest;mitotic spindle assembly checkpoint;reciprocal meiotic recombination;signal transduction;intrinsic apoptotic signaling pathway in response to DNA damage;response to ionizing radiation;regulation of autophagy;positive regulation of gene expression;histone phosphorylation;peptidyl-serine phosphorylation;positive regulation of cell migration;negative regulation of B cell proliferation;regulation of telomere maintenance via telomerase;positive regulation of telomere maintenance via telomerase;positive regulation of histone phosphorylation;phosphatidylinositol-3-phosphate biosynthetic process;peptidyl-serine autophosphorylation;regulation of apoptotic process;positive regulation of apoptotic process;positive regulation of DNA damage response, signal transduction by p53 class mediator;positive regulation of neuron apoptotic process;positive regulation of cell adhesion;positive regulation of transcription by RNA polymerase II;protein autophosphorylation;regulation of telomerase activity;histone mRNA catabolic process;cellular response to retinoic acid;cellular response to gamma radiation;cellular response to X-ray;cellular response to nitrosative stress;signal transduction involved in mitotic G2 DNA damage checkpoint;replicative senescence;establishment of RNA localization to telomere;establishment of protein-containing complex localization to telomere;regulation of cellular response to heat;regulation of signal transduction by p53 class mediator;positive regulation of DNA catabolic process;regulation of microglial cell activation;negative regulation of TORC1 signaling;negative regulation of telomere capping;positive regulation of telomere maintenance via telomere lengthening;positive regulation of telomerase catalytic core complex assembly;regulation of cellular response to gamma radiation
Cellular component
chromosome, telomeric region;nuclear chromosome, telomeric region;nucleus;nucleoplasm;nucleolus;cytoplasmic vesicle;DNA repair complex
Molecular function
DNA binding;protein serine/threonine kinase activity;DNA-dependent protein kinase activity;protein binding;ATP binding;1-phosphatidylinositol-3-kinase activity;protein-containing complex binding;protein dimerization activity;protein N-terminus binding