PTEN hamartoma tumor syndrome

Summary

PTEN hamartoma tumor syndrome (MONDO:0017623) is a cancer with 8 cohort genes (2 CIViC-evidence somatic drivers; 2,129 ClinVar predisposition records) and 9 clinical trials. Top therapeutic interventions include everolimus.

At a glance

• Classification: Cancer
• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 8
• ClinVar variants: 2,129
• Clinical trials: 9

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	9	Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	PTEN hamartoma tumor syndrome
Mondo ID	MONDO:0017623
Orphanet	306498
DOID	DOID:0080191
NCIT	C179915
SNOMED CT	722859001
UMLS	C1959582
MedGen	368366
GARD	0012800
NORD	1631
Is cancer (heuristic)	yes

Also known as: PHTS · PTEN hamartoma tumor syndrome · PTEN-related Hamartoma tumor syndrome

Data availability: 2,129 ClinVar variants · 211 ClinGen variant curations.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › PTEN hamartoma tumor syndrome

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Subtypes (4): Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome, Proteus-like syndrome

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

600 retrieved; paginated sample, class counts are floors:

183 uncertain significance, 142 pathogenic, 121 likely benign, 54 conflicting classifications of pathogenicity, 46 benign/likely benign, 30 likely pathogenic, 16 pathogenic/likely pathogenic, 7 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068715	NC_000010.10:g.(?89621800)(89693018_?)del	KLLN	Pathogenic	criteria provided, single submitter
1014805	NM_000314.8(PTEN):c.801G>C (p.Lys267Asn)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1018969	NM_000314.8(PTEN):c.141_142inv (p.Arg47_Asn48delinsSerHis)	PTEN	Pathogenic	criteria provided, single submitter
1067089	NM_000314.8(PTEN):c.376G>C (p.Ala126Pro)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1067224	NM_000314.8(PTEN):c.523G>A (p.Val175Met)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1067457	NC_000010.10:g.(?89685260)(89685324_?)del	PTEN	Pathogenic	criteria provided, single submitter
1067498	NM_000314.8(PTEN):c.493G>C (p.Gly165Arg)	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068214	NM_000314.8(PTEN):c.75G>C (p.Leu25Phe)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1068748	NM_000314.8(PTEN):c.440del (p.Lys147fs)	PTEN	Pathogenic	criteria provided, single submitter
1069185	NC_000010.10:g.89711945_89711946insAlu	PTEN	Pathogenic	criteria provided, single submitter
1069313	NM_000314.8(PTEN):c.224_233del (p.His75fs)	PTEN	Pathogenic	criteria provided, single submitter
1069314	NM_000314.8(PTEN):c.502_503del (p.Ile168fs)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1069418	NM_000314.8(PTEN):c.688_689dup (p.Pro231fs)	PTEN	Pathogenic	criteria provided, single submitter
1069915	NM_000314.8(PTEN):c.184A>T (p.Lys62Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1070574	NM_000314.8(PTEN):c.158_162dup (p.Arg55Ter)	PTEN	Pathogenic	criteria provided, single submitter
1070828	NM_000314.8(PTEN):c.49_61dup (p.Phe21fs)	PTEN	Pathogenic	criteria provided, single submitter
1070951	NM_000314.8(PTEN):c.301del (p.Ile101fs)	PTEN	Pathogenic	criteria provided, single submitter
1071470	NM_000314.8(PTEN):c.260_261dup (p.Tyr88fs)	PTEN	Pathogenic	criteria provided, single submitter
1072116	NM_000314.8(PTEN):c.641del (p.Gln214fs)	PTEN	Pathogenic	criteria provided, single submitter
1072117	NM_000314.8(PTEN):c.672dup (p.Tyr225fs)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1072198	NM_000314.8(PTEN):c.492+1G>C	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073539	NM_000314.8(PTEN):c.628del (p.Thr210fs)	PTEN	Pathogenic	criteria provided, single submitter
1073577	NM_000314.8(PTEN):c.17_20dup (p.Ile8fs)	PTEN	Pathogenic	criteria provided, single submitter
1074078	NM_000314.8(PTEN):c.304A>T (p.Lys102Ter)	PTEN	Pathogenic	criteria provided, single submitter
1074735	NM_000314.8(PTEN):c.989_992del (p.Lys330fs)	PTEN	Pathogenic	criteria provided, single submitter
1075090	NM_000314.8(PTEN):c.785dup (p.Asn262fs)	PTEN	Pathogenic	criteria provided, single submitter
1075679	NM_000314.8(PTEN):c.536_539dup (p.Tyr180Ter)	PTEN	Pathogenic	criteria provided, single submitter
1075939	NM_000314.8(PTEN):c.250A>T (p.Arg84Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1076052	NM_000314.8(PTEN):c.562_563insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTCAGGAGATCGAGACCATCNAAAAAAAAAAAAAAAAAAAAAA (p.Tyr188fs)	PTEN	Pathogenic	criteria provided, single submitter
1076154	NM_000314.8(PTEN):c.547_548del (p.Lys183fs)	PTEN	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
KLLN			CIViC #32083
PTEN	LoF	ANGS,BLCA,BRCA,CCRCC,CEAD,CESC,CHOL,CHRCC,COADREAD,CSCC,ESCA,GB,GBM,HCC,HGGNOS,HNSC,LGGNOS,LIPO,LUAD,LUSC,MBL,MEL,MT,NSCLC,OVT,PANET,PAST,PRAD,PRCC,PROSTATE,RCC,SCLC,SKCM,SOFT_TISSUE,STAD,UCEC,UCS,WDTC	CIViC #41

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NUTM2A	Orphanet:213711	Endometrial stromal sarcoma
LIPN	Orphanet:313	Lamellar ichthyosis
ATAD1	Orphanet:3197	Hereditary hyperekplexia
KLLN	Orphanet:201	Cowden syndrome
KLLN	Orphanet:227535	Hereditary breast cancer
PTEN	Orphanet:109	Bannayan-Riley-Ruvalcaba syndrome
PTEN	Orphanet:137608	Segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome
PTEN	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
PTEN	Orphanet:201	Cowden syndrome
PTEN	Orphanet:210548	Macrocephaly-intellectual disability-autism syndrome
PTEN	Orphanet:2969	Proteus-like syndrome
PTEN	Orphanet:494547	Squamous cell carcinoma of the hypopharynx
PTEN	Orphanet:494550	Squamous cell carcinoma of the larynx
PTEN	Orphanet:500464	Squamous cell carcinoma of the nasal cavity and paranasal sinuses
PTEN	Orphanet:500478	Squamous cell carcinoma of the oropharynx
PTEN	Orphanet:502363	Squamous cell carcinoma of the oral cavity
PTEN	Orphanet:502366	Squamous cell carcinoma of the lip
PTEN	Orphanet:65285	Lhermitte-Duclos disease
PTEN	Orphanet:79076	Juvenile polyposis of infancy

Cohort genes → proteins

8 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NUTM2A	HGNC:23438	ENSG00000184923	Q8IVF1	NUT family member 2A	clinvar
LIPN	HGNC:23452	ENSG00000204020	Q5VXI9	Lipase member N	clinvar
ATAD1	HGNC:25903	ENSG00000138138	Q8NBU5	Outer mitochondrial transmembrane helix translocase	clinvar
SHLD2	HGNC:28773	ENSG00000122376	Q86V20	Shieldin complex subunit 2	clinvar
KLLN	HGNC:37212	ENSG00000227268	B2CW77	Killin	clinvar
ADIRF-AS1	HGNC:45127	ENSG00000272734		ADIRF antisense RNA 1	clinvar
MLDHR	HGNC:55481	ENSG00000289051	C0HLV8	PTEN upstream open reading frame MP31	clinvar
PTEN	HGNC:9588	ENSG00000171862	P60484	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LIPN	Lipase member N	Plays a highly specific role in the last step of keratinocyte differentiation.
ATAD1	Outer mitochondrial transmembrane helix translocase	Outer mitochondrial translocase required to remove mislocalized tail-anchored transmembrane proteins on mitochondria.
SHLD2	Shieldin complex subunit 2	Component of the shieldin complex, which plays an important role in repair of DNA double-stranded breaks (DSBs).
KLLN	Killin	DNA-binding protein involved in S phase checkpoint control-coupled apoptosis by mediating p53/TP53-induced apoptosis.
MLDHR	PTEN upstream open reading frame MP31	Inhibits lactate dehydrogenase (LDH)-mediated conversion of lactate to pyruvate in mitochondria by competing with mitochondrial LDH for binding to NAD(+).
PTEN	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	Dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 7 · Druggable fraction: 0.12

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
Phosphatase	1	10.5×	0.091
Other/Unknown	7	1.6×	0.091

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NUTM2A	Other/Unknown	no		NUT_N, NUT
LIPN	Other/Unknown	no		AB_hydrolase_1, Lipase_euk, AB_hydrolase_fold
ATAD1	Other/Unknown	no		AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
SHLD2	Other/Unknown	no		FAM35A, SHLD2_C, SHLD2_OB1
KLLN	Other/Unknown	no
ADIRF-AS1	Other/Unknown	no
MLDHR	Other/Unknown	no		MP31
PTEN	Phosphatase	yes	3.1.3.16	Tyr_Pase_dom, Tyr_Pase_cat, Tensin_C2-dom

Expression context

Cohort genes with no expression data: 1.

5 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)	7
unknown	1

Top tissues across cohort

Tissue	Cohort genes
skin of abdomen	2
left testis	2
calcaneal tendon	2
apex of heart	1
prefrontal cortex	1
sural nerve	1
leukocyte	1
monocyte	1
islet of Langerhans	1
right testis	1
duodenum	1
endometrium	1
male germ line stem cell (sensu Vertebrata) in testis	1
pancreatic ductal cell	1
tibialis anterior	1
skin of leg	1
endothelial cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NUTM2A	131		yes	sural nerve, apex of heart, prefrontal cortex
LIPN	88	tissue_specific	yes	monocyte, leukocyte, skin of abdomen
ATAD1	252	ubiquitous	marker	right testis, left testis, islet of Langerhans
SHLD2	141	ubiquitous	marker	calcaneal tendon, endometrium, duodenum
KLLN	149		marker	tibialis anterior, male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell
ADIRF-AS1	170	ubiquitous	marker	skin of leg, skin of abdomen, left testis
MLDHR
PTEN	256	ubiquitous	marker	sperm, endothelial cell, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTEN	11,626
ATAD1	3,099
LIPN	1,288
NUTM2A	539
SHLD2	517
KLLN	234
ADIRF-AS1	0
MLDHR	0

Intra-cohort edges

A	B	Sources
KLLN	PTEN	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 4 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTEN	P60484	12
SHLD2	Q86V20	3
ATAD1	Q8NBU5	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LIPN	Q5VXI9	92.14
MLDHR	C0HLV8	83.86
KLLN	B2CW77	51.20
NUTM2A	Q8IVF1	47.48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 8 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
PTEN Loss of Function in Cancer	1	1903.3×	0.009	PTEN
Regulation of PTEN mRNA translation	1	380.7×	0.017	PTEN
Regulation of PTEN localization	1	346.1×	0.017	PTEN
Class I peroxisomal membrane protein import	1	173.0×	0.024	ATAD1
Synthesis of IP3 and IP4 in the cytosol	1	141.0×	0.024	PTEN
Transcriptional Regulation by MECP2	1	105.7×	0.024	PTEN
Negative regulation of the PI3K/AKT network	1	92.8×	0.024	PTEN
Ovarian tumor domain proteases	1	92.8×	0.024	PTEN
Synthesis of PIPs at the plasma membrane	1	70.5×	0.025	PTEN
Protein localization	1	63.4×	0.025	ATAD1
Regulation of PTEN stability and activity	1	61.4×	0.025	PTEN
Regulation of PTEN gene transcription	1	59.5×	0.025	PTEN
TP53 Regulates Metabolic Genes	1	43.3×	0.030	PTEN
Downstream TCR signaling	1	42.8×	0.030	PTEN
Formation of the cornified envelope	1	29.3×	0.041	LIPN
Keratinization	1	18.6×	0.059	LIPN
Ub-specific processing proteases	1	17.7×	0.059	PTEN
Developmental Biology	1	4.8×	0.194	LIPN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
extraction of mislocalized protein from mitochondrial outer membrane	1	2808.7×	0.014	ATAD1
negative regulation of synaptic vesicle clustering	1	1404.3×	0.014	PTEN
negative regulation of keratinocyte migration	1	936.2×	0.014	PTEN
somatic diversification of immunoglobulins involved in immune response	1	702.2×	0.014	SHLD2
rhythmic synaptic transmission	1	702.2×	0.014	PTEN
central nervous system myelin maintenance	1	468.1×	0.014	PTEN
negative regulation of oxidative phosphorylation	1	401.2×	0.014	MLDHR
negative regulation of cell cycle G1/S phase transition	1	401.2×	0.014	PTEN
negative regulation of wound healing, spreading of epidermal cells	1	401.2×	0.014	PTEN
spindle assembly involved in female meiosis	1	312.1×	0.014	PTEN
central nervous system neuron axonogenesis	1	312.1×	0.014	PTEN
telomere maintenance in response to DNA damage	1	312.1×	0.014	SHLD2
postsynaptic density assembly	1	312.1×	0.014	PTEN
neuron-neuron synaptic transmission	1	280.9×	0.014	PTEN
negative regulation of peptidyl-serine phosphorylation	1	280.9×	0.014	PTEN
negative regulation of cell size	1	280.9×	0.014	PTEN
negative regulation of synaptic transmission, glutamatergic	1	280.9×	0.014	ATAD1
presynaptic membrane assembly	1	280.9×	0.014	PTEN
negative regulation of organ growth	1	234.1×	0.014	PTEN
forebrain morphogenesis	1	234.1×	0.014	PTEN
multicellular organismal response to stress	1	216.1×	0.014	PTEN
positive regulation of isotype switching	1	216.1×	0.014	SHLD2
negative regulation of axonogenesis	1	216.1×	0.014	PTEN
cellular response to electrical stimulus	1	216.1×	0.014	PTEN
negative regulation of excitatory postsynaptic potential	1	216.1×	0.014	PTEN
maternal behavior	1	187.2×	0.015	PTEN
prepulse inhibition	1	187.2×	0.015	PTEN
locomotor rhythm	1	175.5×	0.015	PTEN
cornification	1	175.5×	0.015	LIPN
regulation of double-strand break repair via homologous recombination	1	165.2×	0.015	SHLD2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 8

Druggability breadth: 1 of 8 evidence-associated genes (12%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NUTM2A	0	0
LIPN	0	0
ATAD1	0	0
SHLD2	0	0
KLLN	0	0
ADIRF-AS1	0	0
MLDHR	0	0
PTEN	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PTEN	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PTEN	3.1.3.16, 3.1.3.67	protein-serine/threonine phosphatase, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PTEN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	7	NUTM2A, LIPN, ATAD1, SHLD2, KLLN, ADIRF-AS1, MLDHR

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NUTM2A	0	—
LIPN	0	—
ATAD1	0	—
SHLD2	0	—
KLLN	0	—
ADIRF-AS1	0	—
MLDHR	0	—
PTEN	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 9.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE1/PHASE2	2
PHASE2/PHASE3	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07218575	PHASE2/PHASE3	NOT_YET_RECRUITING	Double-Blind Trial of Everolimus for Improving Social Abilities in PTEN Germline Mutations
NCT02991807	PHASE1/PHASE2	COMPLETED	RAD001 and Neurocognition in PTEN Hamartoma Tumor Syndrome
NCT04094675	PHASE2	COMPLETED	Sirolimus for Cowden Syndrome With Colon Polyposis
NCT06080165	PHASE1/PHASE2	WITHDRAWN	Sirolimus for Improving Social Abilities in People With PTEN Germline Mutations
NCT02461446	Not specified	RECRUITING	Natural History Study of Individuals With Autism and Germline Heterozygous PTEN Mutations
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT06462430	Not specified	RECRUITING	PTEN Hamartoma Tumor Syndrome Pediatric Patient Registry
NCT03630523	Not specified	UNKNOWN	Response of Immune System to Flu Vaccination in PHTS
NCT05671107	Not specified	COMPLETED	Development and Validation of an Online Neurobehavioral Evaluation Tool for PTEN Patients

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EVEROLIMUS	4	2