Leukemia, acute myeloid, susceptibility to

Summary

Leukemia, acute myeloid, susceptibility to (MONDO:0100173) is a cancer with 3 cohort genes (3 CIViC-evidence somatic drivers; 7 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Cohort genes: 3
• ClinVar variants: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	leukemia, acute myeloid, susceptibility to
Mondo ID	MONDO:0100173
UMLS	C3275959
MedGen	477590
GARD	0027994
Is cancer (heuristic)	yes

Data availability: 7 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › leukemia, acute myeloid, susceptibility to

Related subtypes (116): mosaic variegated aneuploidy syndrome, tuberous sclerosis, hereditary breast ovarian cancer syndrome, hereditary multiple osteochondromas, nevoid basal cell carcinoma syndrome, leukemia, chronic lymphocytic, susceptibility to, 2, blue rubber bleb nevus, cherubism, Beckwith-Wiedemann syndrome, multiple self-healing squamous epithelioma, erythroleukemia, familial, susceptibility to, goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, hyperparathyroidism 2 with jaw tumors, Kaposi sarcoma, susceptibility to, hereditary leiomyomatosis and renal cell cancer, susceptibility to uveal melanoma, melanoma and neural system tumor syndrome, nasopharyngeal carcinoma, susceptibility to, 2, WAGR syndrome, neuroblastoma, susceptibility to, 1, Rothmund-Thomson syndrome, mismatch repair cancer syndrome 1, Wiskott-Aldrich syndrome, N syndrome, hereditary thrombocytopenia and hematologic cancer predisposition syndrome, prostate cancer/brain cancer susceptibility, Brooke-Spiegler syndrome, pancreatic cancer, susceptibility to, 1, Carney-Stratakis syndrome, nasopharyngeal carcinoma, susceptibility to, 1, ovarian cancer, susceptibility to, 1, colorectal cancer, susceptibility to, 1, lung cancer susceptibility 1, leukemia, chronic lymphocytic, susceptibility to, 1, Kostmann syndrome, colorectal cancer, susceptibility to, 2, colorectal cancer, susceptibility to, 3, colorectal cancer, susceptibility to, 5, colorectal cancer, susceptibility to, 6, colorectal cancer, susceptibility to, 7, leukemia, chronic lymphocytic, susceptibility to, 3, leukemia, chronic lymphocytic, susceptibility to, 4, leukemia, chronic lymphocytic, susceptibility to, 5, lung cancer susceptibility 3, colorectal cancer, susceptibility to, 8, colorectal cancer, susceptibility to, 9, colorectal cancer, susceptibility to, 10, colorectal cancer, susceptibility to, 11, lung cancer susceptibility 4, neuroblastoma, susceptibility to, 3, neuroblastoma, susceptibility to, 4, neuroblastoma, susceptibility to, 5, neuroblastoma, susceptibility to, 6, leukemia, acute lymphocytic, susceptibility to, 1, leukemia, acute lymphocytic, susceptibility to, 2, lung cancer susceptibility 5, BAP1-related tumor predisposition syndrome, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Maffucci syndrome, basal cell carcinoma, susceptibility to, 7, colorectal cancer, susceptibility to, 12, leukemia, acute lymphoblastic, susceptibility to, 3, cholangiocarcinoma, susceptibility to, progeroid features-hepatocellular carcinoma predisposition syndrome, neuroblastoma, susceptibility to, 7, DDX41-related hematologic malignancy predisposition syndrome, nasopharyngeal carcinoma, susceptibility to, 3, familial isolated hyperparathyroidism, intestinal polyposis syndrome, dyskeratosis congenita, familial rhabdoid tumor, multiple endocrine neoplasia, hereditary pheochromocytoma-paraganglioma, PTEN hamartoma tumor syndrome, familial multiple fibrofolliculoma, hereditary retinoblastoma, familial atypical multiple mole melanoma syndrome, hereditary nonpolyposis colon cancer, Li-Fraumeni syndrome, Cobb syndrome, neurofibromatosis, susceptibility to familial cutaneous melanoma, pancreatic cancer, susceptibility to, 5, diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, glioma susceptibility, hemangioma, capillary infantile, susceptibility to, CDH1-related diffuse gastric and lobular breast cancer syndrome, NTHL1-deficiency tumor predisposition syndrome, SAMD9-related spectrum and myeloid neoplasm risk, neuroblastoma, susceptibility to, 2, BARD1-related cancer predisposition, BRCA1-related cancer predisposition, BRCA2-related cancer predisposition, ATM-related cancer predisposition, CHEK2-related cancer predisposition, PALB2-related cancer predisposition, RAD51C-related cancer predisposition, RAD51D-related cancer predisposition, Li-fraumeni-like syndrome, breast cancer, familial, susceptibility to, 1, breast cancer, familial, susceptibility to, 2, breast cancer, familial, susceptibility to, 3, colorectal cancer, susceptibility to, 4, colorectal cancer, susceptibility to, on chromosome 15, ovarian cancer, familial, susceptibility to, 1, ovarian cancer, familial, susceptibility to, 2, ovarian cancer, familial, susceptibility to, 3, inherited hematologic cancer-predisposing syndrome, mosaic neurofibromatosis/schwannomatosis, tumor predisposition syndrome 2, prostate cancer, hereditary, X-linked 3, follicular lymphoma, susceptibility to, GPR161-related medulloblastoma predisposition, SAMD9L-related spectrum and myeloid neoplasm risk, HAVCR2-related cancer predisposition, EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

7 retrieved; paginated sample, class counts are floors:

2 likely pathogenic, 2 conflicting classifications of pathogenicity, 2 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
29709	NM_032638.5(GATA2):c.1192C>T (p.Arg398Trp)	GATA2	Pathogenic	criteria provided, multiple submitters, no conflicts
29711	NM_032638.5(GATA2):c.1061C>T (p.Thr354Met)	GATA2	Pathogenic	criteria provided, multiple submitters, no conflicts
435281	NM_032638.5(GATA2):c.1084C>T (p.Arg362Ter)	GATA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
211061	NM_032638.5(GATA2):c.1054T>C (p.Cys352Arg)	GATA2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
435282	NM_032638.5(GATA2):c.1081C>G (p.Arg361Gly)	GATA2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
211062	NM_032638.5(GATA2):c.857C>T (p.Ala286Val)	GATA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
39121	NM_198253.3(TERT):c.3184G>A (p.Ala1062Thr)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 19 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
FLT3	Act	ALL,AML	CIViC #24
TERT	Act	PRCC	CIViC #79
GATA2	Act	AML,HNSC	CIViC #25

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FLT3	Limited	Autosomal dominant	leukemia, acute myeloid, susceptibility to

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FLT3	Orphanet:102724	Acute myeloid leukemia with t(8;21)(q22;q22) translocation
FLT3	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
FLT3	Orphanet:589534	Mixed phenotype acute leukemia with t(9;22)(q34.1;q11.2)
FLT3	Orphanet:589595	Mixed phenotype acute leukemia with t(v;11q23.3)
FLT3	Orphanet:98829	Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22)
FLT3	Orphanet:98832	Acute myeloid leukemia with minimal differentiation
FLT3	Orphanet:98833	Acute myeloblastic leukemia without maturation
FLT3	Orphanet:98834	Acute myeloblastic leukemia with maturation
FLT3	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia
TERT	Orphanet:146	Differentiated thyroid carcinoma
TERT	Orphanet:1501	Adrenocortical carcinoma
TERT	Orphanet:1775	Dyskeratosis congenita
TERT	Orphanet:2032	Idiopathic pulmonary fibrosis
TERT	Orphanet:2495	Meningioma
TERT	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
TERT	Orphanet:457246	Clear cell sarcoma of kidney
TERT	Orphanet:618	Familial melanoma
TERT	Orphanet:88	Idiopathic aplastic anemia
GATA2	Orphanet:228423	GATA2 deficiency spectrum

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FLT3	HGNC:3765	ENSG00000122025	P36888	Receptor-type tyrosine-protein kinase FLT3	gencc
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	clinvar
GATA2	HGNC:4171	ENSG00000179348	P23769	Endothelial transcription factor GATA-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FLT3	Receptor-type tyrosine-protein kinase FLT3	Tyrosine-protein kinase that acts as a cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells.
TERT	Telomerase reverse transcriptase	Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes.
GATA2	Endothelial transcription factor GATA-2	Transcriptional activator which regulates endothelin-1 gene expression in endothelial cells.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	9.2×	0.313
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FLT3	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD
GATA2	Transcription factor	no		Znf_GATA, Znf_NHR/GATA, TF_GATA-2/3

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
male germ line stem cell (sensu Vertebrata) in testis	1
olfactory bulb	1
stromal cell of endometrium	1
type B pancreatic cell	1
left uterine tube	1
right lung	1
seminal vesicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FLT3	166	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, cerebellar hemisphere, cerebellar cortex
TERT	105	broad	yes	stromal cell of endometrium, type B pancreatic cell, olfactory bulb
GATA2	273	ubiquitous	marker	seminal vesicle, right lung, left uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TERT	5,717
GATA2	4,979
FLT3	3,570

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TERT	O14746	23
FLT3	P36888	11
GATA2	P23769	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 43. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
FLT3 mutants bind TKIs	1	3806.7×	8e-04	FLT3
KW2449-resistant FLT3 mutants	1	3806.7×	8e-04	FLT3
semaxanib-resistant FLT3 mutants	1	3806.7×	8e-04	FLT3
crenolanib-resistant FLT3 mutants	1	3806.7×	8e-04	FLT3
gilteritinib-resistant FLT3 mutants	1	3806.7×	8e-04	FLT3
lestaurtinib-resistant FLT3 mutants	1	3806.7×	8e-04	FLT3
midostaurin-resistant FLT3 mutants	1	3806.7×	8e-04	FLT3
pexidartinib-resistant FLT3 mutants	1	3806.7×	8e-04	FLT3
ponatinib-resistant FLT3 mutants	1	3806.7×	8e-04	FLT3
quizartinib-resistant FLT3 mutants	1	3806.7×	8e-04	FLT3
sorafenib-resistant FLT3 mutants	1	3806.7×	8e-04	FLT3
sunitinib-resistant FLT3 mutants	1	3806.7×	8e-04	FLT3
tandutinib-resistant FLT3 mutants	1	3806.7×	8e-04	FLT3
linifanib-resistant FLT3 mutants	1	3806.7×	8e-04	FLT3
tamatinib-resistant FLT3 mutants	1	3806.7×	8e-04	FLT3
STAT5 Activation	1	543.8×	0.004	FLT3
FLT3 signaling through SRC family kinases	1	543.8×	0.004	FLT3
FLT3 signaling by CBL mutants	1	543.8×	0.004	FLT3
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	543.8×	0.004	TERT
STAT5 activation downstream of FLT3 ITD mutants	1	380.7×	0.006	FLT3
Signaling by FLT3 ITD and TKD mutants	1	253.8×	0.008	FLT3
Negative regulation of FLT3	1	237.9×	0.008	FLT3
Extension of Telomeres	1	200.3×	0.009	TERT
Telomere Extension By Telomerase	1	152.3×	0.012	TERT
Telomere Maintenance	1	122.8×	0.014	TERT
FLT3 Signaling	1	115.3×	0.014	FLT3
PI3K Cascade	1	90.6×	0.018	FLT3
Chromosome Maintenance	1	70.5×	0.022	TERT
MITF-M-dependent gene expression	1	60.4×	0.024	TERT
Constitutive Signaling by Aberrant PI3K in Cancer	1	42.3×	0.033	FLT3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of endothelial cell apoptotic process	2	330.4×	0.001	TERT, GATA2
positive regulation of miRNA transcription	2	193.7×	0.002	TERT, GATA2
RNA-templated transcription	1	5617.3×	0.002	TERT
DNA strand elongation	1	5617.3×	0.002	TERT
semicircular canal development	1	5617.3×	0.002	GATA2
siRNA transcription	1	5617.3×	0.002	TERT
positive regulation of transdifferentiation	1	5617.3×	0.002	TERT
regulation of forebrain neuron differentiation	1	5617.3×	0.002	GATA2
positive regulation of angiogenesis	2	77.0×	0.003	TERT, GATA2
RNA-templated DNA biosynthetic process	1	2808.7×	0.003	TERT
regulation of primitive erythrocyte differentiation	1	2808.7×	0.003	GATA2
eosinophil fate commitment	1	2808.7×	0.003	GATA2
positive regulation of hair cycle	1	2808.7×	0.003	TERT
leukocyte homeostasis	1	1872.4×	0.004	FLT3
ventral spinal cord interneuron differentiation	1	1872.4×	0.004	GATA2
cell differentiation in hindbrain	1	1872.4×	0.004	GATA2
pro-B cell differentiation	1	1404.3×	0.004	FLT3
negative regulation of hematopoietic progenitor cell differentiation	1	1404.3×	0.004	GATA2
GABAergic neuron differentiation	1	1123.5×	0.005	GATA2
commitment of neuronal cell to specific neuron type in forebrain	1	936.2×	0.005	GATA2
thyroid-stimulating hormone-secreting cell differentiation	1	936.2×	0.005	GATA2
negative regulation of brown fat cell differentiation	1	936.2×	0.005	GATA2
positive regulation of protein localization to nucleolus	1	936.2×	0.005	TERT
glandular epithelial cell maturation	1	802.5×	0.005	GATA2
myeloid progenitor cell differentiation	1	802.5×	0.005	FLT3
response to lipid	1	802.5×	0.005	GATA2
lymphocyte proliferation	1	802.5×	0.005	FLT3
negative regulation of macrophage differentiation	1	702.2×	0.005	GATA2
establishment of protein localization to telomere	1	702.2×	0.005	TERT
siRNA processing	1	624.1×	0.005	TERT

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
FLT3	PONATINIB
TERT	BERBERINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FLT3	143	4
TERT	10	4
GATA2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	FLT3
AFATINIB	4	FLT3
FEDRATINIB	4	FLT3
TIVOZANIB	4	FLT3
AXITINIB	4	FLT3
SORAFENIB	4	FLT3
NERATINIB	4	FLT3
INFIGRATINIB PHOSPHATE	4	FLT3
INFIGRATINIB	4	FLT3
IBRUTINIB	4	FLT3
PALBOCICLIB	4	FLT3
REGORAFENIB	4	FLT3
ENTRECTINIB	4	FLT3
PACRITINIB	4	FLT3
FOSTAMATINIB	4	FLT3
QUIZARTINIB DIHYDROCHLORIDE	4	FLT3
CABOZANTINIB	4	FLT3
CERITINIB	4	FLT3
VANDETANIB	4	FLT3
NILOTINIB	4	FLT3
BOSUTINIB	4	FLT3
FILGOTINIB	4	FLT3
ABEMACICLIB	4	FLT3
GILTERITINIB	4	FLT3
BRIGATINIB	4	FLT3
PEXIDARTINIB	4	FLT3
PRALSETINIB	4	FLT3
PAZOPANIB	4	FLT3
NINTEDANIB	4	FLT3
SUNITINIB	4	FLT3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
FLT3	3,132	Binding:3096, Functional:24, ADMET:8, Toxicity:4
TERT	391	Binding:389, Functional:2
GATA2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FLT3	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
FLT3	3,132
TERT	391

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Drug repurposing candidates

30 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Compound	Max phase	Cohort target (bioactivity)
PONATINIB	4	FLT3
AFATINIB	4	FLT3
FEDRATINIB	4	FLT3
TIVOZANIB	4	FLT3
AXITINIB	4	FLT3
SORAFENIB	4	FLT3
NERATINIB	4	FLT3
INFIGRATINIB PHOSPHATE	4	FLT3
INFIGRATINIB	4	FLT3
IBRUTINIB	4	FLT3
PALBOCICLIB	4	FLT3
REGORAFENIB	4	FLT3
ENTRECTINIB	4	FLT3
PACRITINIB	4	FLT3
FOSTAMATINIB	4	FLT3
QUIZARTINIB DIHYDROCHLORIDE	4	FLT3
CABOZANTINIB	4	FLT3
CERITINIB	4	FLT3
VANDETANIB	4	FLT3
NILOTINIB	4	FLT3
BOSUTINIB	4	FLT3
FILGOTINIB	4	FLT3
ABEMACICLIB	4	FLT3
GILTERITINIB	4	FLT3
BRIGATINIB	4	FLT3
PEXIDARTINIB	4	FLT3
PRALSETINIB	4	FLT3
PAZOPANIB	4	FLT3
NINTEDANIB	4	FLT3
SUNITINIB	4	FLT3

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	FLT3, TERT
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GATA2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GATA2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.