Hereditary nonpolyposis colon cancer

disease

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Also known as colorectal cancer, hereditary nonpolyposisfamilial nonpolyposis colon cancerfamilial nonpolyposis colorectal cancerhereditary nonpolyposis colorectal cancerHereditary nonpolyposis colorectal cancer (HNPCC)HNPCC

Summary

Hereditary nonpolyposis colon cancer (MONDO:0018630) is a cancer (an umbrella term covering 5 Mondo subtypes) with 18 cohort genes (11 CIViC-evidence somatic drivers; 676 ClinVar predisposition records) and 14 clinical trials. The dominant Reactome pathway is Diseases of DNA repair (5 cohort genes).

At a glance

Classification: Cancer
Umbrella term: 5 Mondo subtypes
Cohort genes: 18
ClinVar variants: 676
Clinical trials: 14

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary nonpolyposis colon cancer
Mondo ID	MONDO:0018630
OMIM	120435
Orphanet	443909
ICD-11	8113015
NCIT	C120083
SNOMED CT	315058005
UMLS	C1333990
MedGen	232602
GARD	0025132
Is cancer (heuristic)	yes

Also known as: colorectal cancer, hereditary nonpolyposis · familial nonpolyposis colon cancer · familial nonpolyposis colorectal cancer · hereditary nonpolyposis colon cancer · hereditary nonpolyposis colorectal cancer · Hereditary nonpolyposis colorectal cancer (HNPCC) · HNPCC

Data availability: 676 ClinVar variants · 11 GenCC gene-disease records · 2 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › hereditary nonpolyposis colon cancer

Subtypes (5): Lynch syndrome, Muir-Torre syndrome, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, familial colorectal cancer type X

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:

252 pathogenic, 123 pathogenic/likely pathogenic, 74 conflicting classifications of pathogenicity, 59 likely pathogenic, 42 uncertain significance, 38 benign/likely benign, 7 likely benign, 5 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
439050	NM_000492.4(CFTR):c.1239dup (p.Gln414fs)	CFTR-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1405437	NM_007194.4(CHEK2):c.1335C>A (p.Tyr445Ter)	CHEK2	Pathogenic	criteria provided, multiple submitters, no conflicts
142524	NM_007194.4(CHEK2):c.499G>A (p.Gly167Arg)	CHEK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
185552	NM_007194.4(CHEK2):c.661_664dup (p.Met222fs)	CHEK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
216652	NM_007194.4(CHEK2):c.846+4_846+7del	CHEK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265567	NM_007194.4(CHEK2):c.1170C>A (p.Tyr390Ter)	CHEK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3779072	NM_007194.4(CHEK2):c.1200_1225del (p.Thr401fs)	CHEK2	Pathogenic	criteria provided, single submitter
491651	NM_007194.4(CHEK2):c.893_897del (p.Tyr298fs)	CHEK2	Pathogenic	criteria provided, multiple submitters, no conflicts
1804739	NC_000002.11:g.(47607109_47612304)_(47698202_47702163)del	EPCAM	Pathogenic	criteria provided, single submitter
2573488	NC_000002.11:g.(?47596286)(47710368_?)del	EPCAM	Pathogenic	criteria provided, single submitter
2573489	NC_000002.11:g.(?47596286)(47657081_47672686)del	EPCAM	Pathogenic	criteria provided, single submitter
2573490	NC_000002.11:g.(?47596286)(47614168_?)del	EPCAM	Pathogenic	criteria provided, single submitter
2581277	NC_000002.11:g.(?47596286)(47630542_47635539)del	EPCAM	Pathogenic	criteria provided, single submitter
3385051	NC_000002.11:g.(47607109_47612304)(47614160?)del	EPCAM	Pathogenic	criteria provided, single submitter
3629543	NC_000002.11:g.(47602439_47604152)_(47637512_47639552)del	EPCAM	Pathogenic	criteria provided, single submitter
3895800	NC_000002.11:g.(47607109_47612304)(47613753?)del	EPCAM	Pathogenic	criteria provided, single submitter
6035	NM_005476.7(GNE):c.1892C>T (p.Ala631Val)	GNE	Pathogenic	criteria provided, multiple submitters, no conflicts
1068033	NM_000249.4(MLH1):c.1038+1G>A	MLH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1321455	NC_000003.11:g.(37045966_37048481)_(37048555_37050304)del	MLH1	Pathogenic	criteria provided, single submitter
1343455	NC_000003.11:g.(37061955_37067127)_(37067499_37070274)del	MLH1	Pathogenic	criteria provided, single submitter
1405246	NM_000249.4(MLH1):c.1239dup (p.Glu414fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
142143	NM_000249.4(MLH1):c.984_997del (p.His329fs)	MLH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
142856	NM_000249.4(MLH1):c.117-2A>G	MLH1	Pathogenic	reviewed by expert panel
1677005	NC_000003.11:g.(37061955_37067127)_(37070424_37081676)dup	MLH1	Pathogenic	criteria provided, single submitter
1677109	NC_000003.11:g.(37083823_37089009)_(37089175_37090007)del	MLH1	Pathogenic	criteria provided, single submitter
17080	NM_000249.4(MLH1):c.1846AAG[2] (p.Lys618del)	MLH1	Pathogenic	reviewed by expert panel
17087	NM_000249.4(MLH1):c.676C>T (p.Arg226Ter)	MLH1	Pathogenic	reviewed by expert panel
17099	NM_000249.4(MLH1):c.2041G>A (p.Ala681Thr)	MLH1	Pathogenic	reviewed by expert panel
1779805	NM_000249.4(MLH1):c.1771del (p.Asp591fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
186198	NM_000249.4(MLH1):c.2162del (p.Tyr721fs)	MLH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 79 · Orphanet: 41 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
SMARCA4	Act	BL,BLADDER,BLCA,CCRCC,CHOL,COAD,COADREAD,EGC,ESCA,ESCC,HCC,HNSC,LGGNOS,LUAD,MBL,MLYM,NHL,NSCLC,OVT,PAAD,PANCREAS,PAST,PRCC,SACA,STAD,THYM	CIViC #78
CHEK2	Act	BRCA	CIViC #8950
CDKN1B	LoF	BRCA,HCC,PCM,PRAD,SIC	CIViC #914
CTNNA1	Act	CEAD,COADREAD
NFKBIZ			CIViC #14368
ATM	LoF	BLCA,BRCA,CCRCC,CHOL,CLLSLL,COAD,COADREAD,ESCA,HCC,LUAD,LUSC,MEL,NSCLC,PAAD,PANCREAS,PANET,PCM,PLMESO,PRAD,PROSTATE,STAD,UCEC,UTUC,WDTC	CIViC #69
EPCAM			CIViC #3364
MLH1			CIViC #3532
MSH2			CIViC #3628
MSH6			CIViC #2478
PMS2	ambiguous	HCC	CIViC #4371

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
ATM	Limited	Autosomal dominant	hereditary nonpolyposis colon cancer	14
CDKN1B	Limited	Unknown	hereditary nonpolyposis colon cancer	6
CHEK2	Limited	Unknown	hereditary nonpolyposis colon cancer	5
EPHX1	Limited	Unknown	hereditary nonpolyposis colon cancer	3
FAN1	Limited	Unknown	hereditary nonpolyposis colon cancer	6
NFKBIZ	Limited	Unknown	hereditary nonpolyposis colon cancer
RPS20	Limited	Autosomal dominant	hereditary nonpolyposis colon cancer	6
SMARCA4	Limited	Unknown	hereditary nonpolyposis colon cancer	14
XRCC4	Limited	Unknown	hereditary nonpolyposis colon cancer	6
BLM	Disputed Evidence	Autosomal dominant	hereditary nonpolyposis colon cancer	12
CTNNA1	No Known Disease Relationship	Unknown	hereditary nonpolyposis colon cancer	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RPS20	Orphanet:124	Diamond-Blackfan anemia
RPS20	Orphanet:440437	Familial colorectal cancer Type X
SMARCA4	Orphanet:1465	Coffin-Siris syndrome
SMARCA4	Orphanet:231108	Rhabdoid tumor predisposition syndrome
SMARCA4	Orphanet:370396	Small cell carcinoma of the ovary
SMARCA4	Orphanet:466962	SMARCA4-deficient sarcoma of thorax
CHEK2	Orphanet:1331	Familial prostate cancer
CHEK2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
CHEK2	Orphanet:440437	Familial colorectal cancer Type X
CHEK2	Orphanet:524	Li-Fraumeni syndrome
CHEK2	Orphanet:668	Osteosarcoma
CDKN1B	Orphanet:276152	Multiple endocrine neoplasia type 4
CDKN1B	Orphanet:652	Multiple endocrine neoplasia type 1
CTNNA1	Orphanet:26106	Hereditary diffuse gastric cancer
CTNNA1	Orphanet:99001	Butterfly-shaped pigment dystrophy
BLM	Orphanet:125	Bloom syndrome
XRCC4	Orphanet:436182	Microcephalic primordial dwarfism-insulin resistance syndrome
XRCC4	Orphanet:99812	LIG4 syndrome
FAN1	Orphanet:401996	Karyomegalic interstitial nephritis
EPHX1	Orphanet:238475	Familial hypercholanemia
ATM	Orphanet:100	Ataxia-telangiectasia
ATM	Orphanet:1331	Familial prostate cancer
ATM	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
ATM	Orphanet:227535	Hereditary breast cancer
ATM	Orphanet:370109	Ataxia-telangiectasia variant
ATM	Orphanet:440437	Familial colorectal cancer Type X
ATM	Orphanet:52416	Mantle cell lymphoma
ATM	Orphanet:67038	B-cell chronic lymphocytic leukemia
EPCAM	Orphanet:144	Lynch syndrome
EPCAM	Orphanet:92050	Congenital tufting enteropathy
GNE	Orphanet:3166	Sialuria
GNE	Orphanet:438207	Severe autosomal recessive macrothrombocytopenia
GNE	Orphanet:602	GNE myopathy
MLH1	Orphanet:144	Lynch syndrome
MLH1	Orphanet:252202	Constitutional mismatch repair deficiency syndrome
MSH2	Orphanet:144	Lynch syndrome
MSH2	Orphanet:252202	Constitutional mismatch repair deficiency syndrome
MSH6	Orphanet:144	Lynch syndrome
MSH6	Orphanet:252202	Constitutional mismatch repair deficiency syndrome
PMS2	Orphanet:144	Lynch syndrome
PMS2	Orphanet:252202	Constitutional mismatch repair deficiency syndrome

Cohort genes → proteins

18 cohort genes, 17 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	18

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RPS20	HGNC:10405	ENSG00000008988	P60866	Small ribosomal subunit protein uS10	gencc,clinvar
SMARCA4	HGNC:11100	ENSG00000127616	P51532	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4	gencc,clinvar
CHEK2	HGNC:16627	ENSG00000183765	O96017	Serine/threonine-protein kinase Chk2	gencc,clinvar
CDKN1B	HGNC:1785	ENSG00000111276	P46527	Cyclin-dependent kinase inhibitor 1B	gencc,clinvar
CTNNA1	HGNC:2509	ENSG00000044115	P35221	Catenin alpha-1	gencc,clinvar
BLM	HGNC:1058	ENSG00000197299	P54132	RecQ-like DNA helicase BLM	gencc
XRCC4	HGNC:12831	ENSG00000152422	Q13426	DNA repair protein XRCC4	gencc
FAN1	HGNC:29170	ENSG00000198690	Q9Y2M0	Fanconi-associated nuclease 1	gencc
NFKBIZ	HGNC:29805	ENSG00000144802	Q9BYH8	NF-kappa-B inhibitor zeta	gencc
EPHX1	HGNC:3401	ENSG00000143819	P07099	Epoxide hydrolase 1	gencc
ATM	HGNC:795	ENSG00000149311	Q13315	Serine-protein kinase ATM	gencc
EPCAM	HGNC:11529	ENSG00000119888	P16422	Epithelial cell adhesion molecule	clinvar
GNE	HGNC:23657	ENSG00000159921	Q9Y223	Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase	clinvar
CFTR-AS1	HGNC:40144	ENSG00000232661		CFTR antisense RNA 1	clinvar
MLH1	HGNC:7127	ENSG00000076242	P40692	DNA mismatch repair protein Mlh1	clinvar
MSH2	HGNC:7325	ENSG00000095002	P43246	DNA mismatch repair protein Msh2	clinvar
MSH6	HGNC:7329	ENSG00000116062	P52701	DNA mismatch repair protein Msh6	clinvar
PMS2	HGNC:9122	ENSG00000122512	P54278	Mismatch repair endonuclease PMS2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RPS20	Small ribosomal subunit protein uS10	Component of the small ribosomal subunit.
SMARCA4	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4	ATPase involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
CHEK2	Serine/threonine-protein kinase Chk2	Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks.
CDKN1B	Cyclin-dependent kinase inhibitor 1B	Important regulator of cell cycle progression.
CTNNA1	Catenin alpha-1	Associates with the cytoplasmic domain of a variety of cadherins.
BLM	RecQ-like DNA helicase BLM	ATP-dependent DNA helicase that unwinds double-stranded (ds)DNA in a 3’-5’ direction.
XRCC4	DNA repair protein XRCC4	DNA non-homologous end joining (NHEJ) core factor, required for double-strand break repair and V(D)J recombination.
FAN1	Fanconi-associated nuclease 1	Nuclease required for the repair of DNA interstrand cross-links (ICL) recruited at sites of DNA damage by monoubiquitinated FANCD2.
NFKBIZ	NF-kappa-B inhibitor zeta	Involved in regulation of NF-kappa-B transcription factor complexes.
EPHX1	Epoxide hydrolase 1	Biotransformation enzyme that catalyzes the hydrolysis of arene and aliphatic epoxides to less reactive and more water soluble dihydrodiols by the trans addition of water.
ATM	Serine-protein kinase ATM	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.
EPCAM	Epithelial cell adhesion molecule	May act as a physical homophilic interaction molecule between intestinal epithelial cells (IECs) and intraepithelial lymphocytes (IELs) at the mucosal epithelium for providing immunological barrier as a first line of defense against mucosa…
GNE	Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase	Bifunctional enzyme that possesses both UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase activities, and serves as the initiator of the biosynthetic pathway leading to the production of N-acetylneuraminic acid (NeuAc), a…
MLH1	DNA mismatch repair protein Mlh1	Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR).
MSH2	DNA mismatch repair protein Msh2	Component of the post-replicative DNA mismatch repair system (MMR).
MSH6	DNA mismatch repair protein Msh6	Component of the post-replicative DNA mismatch repair system (MMR).
PMS2	Mismatch repair endonuclease PMS2	Component of the post-replicative DNA mismatch repair system (MMR).

Protein-family classification

Druggable: 6 · Difficult: 1 · Unknown: 11 · 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
Enzyme (other)	4	2.7×	0.229
Kinase	2	3.1×	0.272
Other/Unknown	11	1.1×	0.558
Scaffold/PPI	1	1.0×	0.658

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RPS20	Other/Unknown	no		Ribosomal_uS10, Ribosomal_uS10_euk/arc, Ribosomal_uS10_CS
SMARCA4	Other/Unknown	no		SNF2_N, Bromodomain, Helicase_C-like
CHEK2	Kinase	yes	2.7.11.1	FHA_dom, Prot_kinase_dom, Ser/Thr_kinase_AS
CDKN1B	Other/Unknown	no		CDI_dom, CDI_dom_sf
CTNNA1	Other/Unknown	no		Vinculin_CS, Alpha_catenin, Vinculin/catenin
BLM	Enzyme (other)	yes	3.6.4.12	Helicase_C-like, HRDC_dom, DNA/RNA_helicase_DEAH_CS
XRCC4	Other/Unknown	no		XRCC4_N_sf, DNA_repair_prot_XRCC4, XRCC4-like_C
FAN1	Other/Unknown	no		Rad18_UBZ4, tRNA_endonuc-like_dom_sf, VRR_NUC
NFKBIZ	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, OCA
EPHX1	Enzyme (other)	yes	3.3.2.9	AB_hydrolase_1, Epox_hydrolase-like, Epoxide_hydrolase
ATM	Kinase	yes	2.7.11.1	PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
EPCAM	Enzyme (other)	yes	2.4.1.37	Thyroglobulin_1, Thyroglobulin_1_sf, EpCAM_N
GNE	Enzyme (other)	yes	2.7.1.60	ROK, UDP_GlcNAc_Epimerase_2_dom, UDP-GlcNAc_Epase
CFTR-AS1	Other/Unknown	no
MLH1	Other/Unknown	no		MutL/Mlh/PMS, DNA_mismatch_S5_2-like, Ribsml_uS5_D2-typ_fold_subgr
MSH2	Other/Unknown	no		DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS-lik_N, DNA_mismatch_repair_MutS_core
MSH6	Other/Unknown	no		PWWP_dom, DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS-lik_N
PMS2	Other/Unknown	no		MutL/Mlh/PMS, DNA_mismatch_S5_2-like, Ribsml_uS5_D2-typ_fold_subgr

Expression context

Cohort genes with no expression data: 0.

16 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)	18
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	3
ventricular zone	3
ganglionic eminence	2
primordial germ cell in gonad	2
calcaneal tendon	2
colonic epithelium	2
secondary oocyte	2
pancreatic ductal cell	2
colonic mucosa	2
mucosa of sigmoid colon	2
adult organism	1
left ovary	1
lymph node	1
cervix squamous epithelium	1
cortical plate	1
lower esophagus mucosa	1
pigmented layer of retina	1
retina	1
amniotic fluid	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RPS20	311	ubiquitous	marker	adult organism, left ovary, lymph node
SMARCA4	295	ubiquitous	marker	ganglionic eminence, cortical plate, cervix squamous epithelium
CHEK2	183	ubiquitous	marker	primordial germ cell in gonad, lower esophagus mucosa, male germ line stem cell (sensu Vertebrata) in testis
CDKN1B	301	ubiquitous	marker	pigmented layer of retina, retina, ventricular zone
CTNNA1	305	ubiquitous	marker	colonic epithelium, calcaneal tendon, amniotic fluid
BLM	199	ubiquitous	marker	parotid gland, primordial germ cell in gonad, secondary oocyte
XRCC4	234	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, monocyte, mononuclear cell
FAN1	214	ubiquitous	yes	pancreatic ductal cell, right hemisphere of cerebellum, gastrocnemius
NFKBIZ	253	ubiquitous	marker	epithelial cell of pancreas, pancreatic ductal cell, palpebral conjunctiva
EPHX1	276	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, adrenal cortex
ATM	286	ubiquitous	marker	calcaneal tendon, colonic epithelium, corpus callosum
EPCAM	253	broad	marker	jejunal mucosa, colonic mucosa, mucosa of sigmoid colon
GNE	286	ubiquitous	marker	mucosa of sigmoid colon, colonic mucosa, nasal cavity epithelium
CFTR-AS1	68		yes	body of pancreas, islet of Langerhans, pancreas
MLH1	296	ubiquitous	marker	tibialis anterior, skeletal muscle tissue of rectus abdominis, deltoid
MSH2	278	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone
MSH6	293	ubiquitous	marker	ventricular zone, embryo, ganglionic eminence
PMS2	143	ubiquitous	marker	thymus, prefrontal cortex, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 21.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMARCA4	8,138
ATM	7,383
CHEK2	4,795
CDKN1B	4,635
MSH2	4,537
MLH1	4,435
MSH6	4,091
EPCAM	3,359
CTNNA1	3,128
BLM	3,010

Intra-cohort edges

A	B	Sources
ATM	BLM	string_interaction
ATM	CHEK2	string_interaction
ATM	MLH1	string_interaction
ATM	MSH2	string_interaction
ATM	MSH6	string_interaction
BLM	FAN1	biogrid_interaction
BLM	MLH1	string_interaction
BLM	MSH6	string_interaction
CHEK2	MSH6	string_interaction
EPCAM	MLH1	string_interaction
EPCAM	MSH2	string_interaction
EPCAM	MSH6	string_interaction
EPCAM	PMS2	string_interaction
FAN1	MLH1	biogrid_interaction, intact, string_interaction
FAN1	PMS2	biogrid_interaction, string_interaction
MLH1	MSH2	string_interaction
MLH1	MSH6	string_interaction
MLH1	PMS2	biogrid_interaction, intact, string_interaction
MSH2	MSH6	biogrid_interaction, intact, string_interaction
MSH2	PMS2	string_interaction
MSH6	PMS2	string_interaction

Structural data

PDB: 16 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RPS20	P60866	199
CHEK2	O96017	38
XRCC4	Q13426	35
SMARCA4	P51532	31
MSH2	P43246	30
CDKN1B	P46527	19
FAN1	Q9Y2M0	18
BLM	P54132	15
ATM	Q13315	14
CTNNA1	P35221	10
PMS2	P54278	9
MSH6	P52701	8
MLH1	P40692	7
GNE	Q9Y223	5
EPCAM	P16422	2
NFKBIZ	Q9BYH8	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EPHX1	P07099	95.06

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 213. Enrichment computed across 18 evidence-associated genes (16 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 16 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Diseases of DNA repair	5	178.4×	9e-09	BLM, MLH1, MSH2, MSH6, ATM
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	4	203.9×	3e-07	MLH1, MSH2, MSH6, PMS2
Mismatch Repair	3	535.3×	5e-07	MLH1, MSH2, MSH6
Diseases of Mismatch Repair (MMR)	3	535.3×	5e-07	MLH1, MSH2, MSH6
DNA Repair	5	30.8×	2e-05	BLM, MLH1, MSH2, MSH6, ATM
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	3	152.9×	3e-05	MLH1, MSH2, PMS2
Defective Mismatch Repair Associated With MLH1	2	713.8×	4e-05	MLH1, PMS2
Defective Mismatch Repair Associated With MSH6	2	713.8×	4e-05	MSH2, MSH6
Defective Mismatch Repair Associated With PMS2	2	713.8×	4e-05	MLH1, PMS2
TP53 Regulates Transcription of DNA Repair Genes	4	45.3×	4e-05	MLH1, MSH2, ATM, PMS2
Transcriptional Regulation by TP53	5	19.4×	8e-05	CDKN1B, BLM, MLH1, MSH2, ATM
Defective Mismatch Repair Associated With MSH2	2	475.8×	1e-04	MSH2, MSH6
Meiosis	3	53.5×	4e-04	BLM, MLH1, ATM
RNA Polymerase II Transcription	6	8.4×	6e-04	SMARCA4, CDKN1B, BLM, MLH1, MSH2, ATM
Reproduction	3	35.7×	0.001	BLM, MLH1, ATM
Disease	7	5.7×	0.001	RPS20, CDKN1B, BLM, MLH1, MSH2, MSH6, ATM
Defective homologous recombination repair (HRR) due to PALB2 loss of function	2	119.0×	0.002	BLM, ATM
Diseases of DNA Double-Strand Break Repair	2	102.0×	0.002	BLM, ATM
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	2	102.0×	0.002	BLM, ATM
Gene expression (Transcription)	6	6.7×	0.002	SMARCA4, CDKN1B, BLM, MLH1, MSH2, ATM
Stabilization of p53	2	95.2×	0.002	CHEK2, ATM
p53-Dependent G1 DNA Damage Response	2	89.2×	0.002	CDKN1B, ATM
p53-Dependent G1/S DNA damage checkpoint	2	89.2×	0.002	CDKN1B, ATM
Meiotic recombination	3	24.3×	0.002	BLM, MLH1, ATM
G1/S DNA Damage Checkpoints	2	84.0×	0.002	CDKN1B, ATM
Resolution of D-Loop Structures	2	79.3×	0.002	BLM, ATM
G2/M DNA damage checkpoint	3	22.5×	0.002	CHEK2, BLM, ATM
Regulation of TP53 Activity through Phosphorylation	3	22.1×	0.002	CHEK2, BLM, ATM
Regulation of TP53 Activity through Methylation	2	68.0×	0.003	CHEK2, ATM
Generic Transcription Pathway	6	5.7×	0.003	SMARCA4, CDKN1B, BLM, MLH1, MSH2, ATM

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 17 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
somatic recombination of immunoglobulin gene segments	3	743.5×	3e-07	MSH2, MSH6, PMS2
somatic hypermutation of immunoglobulin genes	4	247.8×	3e-07	MLH1, MSH2, MSH6, PMS2
isotype switching	4	198.3×	3e-07	NFKBIZ, MLH1, MSH2, MSH6
mismatch repair	4	152.5×	7e-07	MLH1, MSH2, MSH6, PMS2
positive regulation of isotype switching to IgA isotypes	3	495.6×	9e-07	MLH1, MSH2, PMS2
positive regulation of isotype switching to IgG isotypes	3	270.4×	6e-06	MLH1, MSH2, PMS2
intrinsic apoptotic signaling pathway in response to DNA damage	4	76.2×	7e-06	CHEK2, MLH1, MSH6, ATM
negative regulation of DNA recombination	3	198.3×	1e-05	BLM, MSH2, MSH6
response to X-ray	3	156.5×	2e-05	BLM, XRCC4, MSH2
double-strand break repair	4	47.8×	3e-05	CHEK2, XRCC4, MSH2, ATM
determination of adult lifespan	3	76.2×	2e-04	MSH2, MSH6, ATM
double-strand break repair via nonhomologous end joining	3	74.3×	2e-04	XRCC4, MLH1, ATM
DNA damage response, signal transduction by p53 class mediator	3	63.3×	3e-04	CHEK2, CDKN1B, ATM
meiotic telomere clustering	2	220.3×	7e-04	MLH1, ATM
DNA double-strand break processing	2	180.2×	9e-04	BLM, ATM
positive regulation of signal transduction by p53 class mediator	2	141.6×	0.001	RPS20, SMARCA4
cellular response to lithium ion	2	132.2×	0.001	CDKN1B, XRCC4
regulation of autophagosome assembly	2	132.2×	0.001	CHEK2, ATM
DNA repair	4	15.0×	0.002	BLM, FAN1, MSH2, MSH6
replicative senescence	2	116.6×	0.002	CHEK2, ATM
mitotic intra-S DNA damage checkpoint signaling	2	110.1×	0.002	CHEK2, MSH2
double-strand break repair via homologous recombination	3	27.5×	0.002	BLM, FAN1, ATM
cellular response to stress	2	99.1×	0.002	CHEK2, ATM
epithelial cell apoptotic process	2	99.1×	0.002	CDKN1B, NFKBIZ
signal transduction in response to DNA damage	2	94.4×	0.002	CHEK2, ATM
regulation of cyclin-dependent protein serine/threonine kinase activity	2	86.2×	0.002	CDKN1B, BLM
cellular response to gamma radiation	2	70.8×	0.004	CHEK2, ATM
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	2	58.3×	0.005	CHEK2, MSH2
mitotic G2 DNA damage checkpoint signaling	2	52.2×	0.006	BLM, ATM
DNA damage checkpoint signaling	2	46.1×	0.007	CHEK2, ATM

Therapeutics

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 7 · Undrugged: 11

Druggability breadth: 14 of 18 evidence-associated genes (78%) 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
RPS20	GENTAMICIN SULFATE
CHEK2	NERATINIB
BLM	AMIFOSTINE
ATM	AMIODARONE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BLM	284	4
ATM	35	4
CHEK2	30	4
SMARCA4	2	2
EPHX1	2	2
RPS20	1	4
MSH6	1	2
CDKN1B	0	0
CTNNA1	0	0
XRCC4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GENTAMICIN SULFATE	4	RPS20
NERATINIB	4	CHEK2
BOSUTINIB	4	CHEK2
BRIGATINIB	4	CHEK2
SUNITINIB	4	CHEK2
GEFITINIB	4	CHEK2
AMIFOSTINE	4	BLM
BEXAROTENE	4	BLM
DICLOFENAC SODIUM	4	BLM
CLOTRIMAZOLE	4	BLM
FLUORESCEIN	4	BLM
OXCARBAZEPINE	4	BLM
BUMETANIDE	4	BLM
GLIPIZIDE	4	BLM
SALMETEROL XINAFOATE	4	BLM
AMIODARONE HYDROCHLORIDE	4	ATM, BLM
INDIGOTINDISULFONATE	4	BLM
TRIHEXYPHENIDYL HYDROCHLORIDE	4	BLM
RALOXIFENE HYDROCHLORIDE	4	BLM
IDARUBICIN	4	BLM
EDROPHONIUM CHLORIDE	4	BLM
PINACIDIL ANHYDROUS	4	BLM
DITHIAZANINE	4	BLM
TRIMETREXATE	4	BLM
NICARDIPINE HYDROCHLORIDE	4	BLM
PILOCARPINE HYDROCHLORIDE	4	BLM
PHENYLEPHRINE HYDROCHLORIDE	4	BLM
APRACLONIDINE HYDROCHLORIDE	4	BLM
DOXYLAMINE SUCCINATE	4	BLM
ROPINIROLE HYDROCHLORIDE	4	BLM

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 6.

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

Symbol	Assays	Type breakdown
CHEK2	690	Binding:687, Functional:2, ADMET:1
ATM	240	Binding:233, Functional:5, ADMET:2
SMARCA4	230	Binding:207, ADMET:12, Functional:11
RPS20	90	Binding:90
BLM	82	Binding:78, Functional:4
EPHX1	30	Binding:18, ADMET:12
MSH6	10	Binding:10
MSH2	9	Binding:9
CDKN1B	5	Binding:5
CTNNA1	2	Binding:2
XRCC4	1	Binding:1
EPCAM	1	Binding:1
GNE	1	Binding:1
PMS2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CHEK2	2.7.11.1	non-specific serine/threonine protein kinase
BLM	3.6.4.12	DNA helicase
EPHX1	3.3.2.9	microsomal epoxide hydrolase
ATM	2.7.11.1	non-specific serine/threonine protein kinase
EPCAM	2.4.1.37, 2.4.1.40	fucosylgalactoside 3-alpha-galactosyltransferase, glycoprotein-fucosylgalactoside alpha-N-acetylgalactosaminyltransferase
GNE	2.7.1.60, 3.2.1.183, 5.1.3.14	N-acylmannosamine kinase, UDP-N-acetylglucosamine 2-epimerase (hydrolysing), UDP-N-acetylglucosamine 2-epimerase (non-hydrolysing)

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SMARCA4	230
CHEK2	690
ATM	240

Pharmacogenomics

Cohort genes with a PharmGKB record: 17; 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)
GENTAMICIN SULFATE	4	RPS20
NERATINIB	4	CHEK2
BOSUTINIB	4	CHEK2
BRIGATINIB	4	CHEK2
SUNITINIB	4	CHEK2
GEFITINIB	4	CHEK2
AMIFOSTINE	4	BLM
BEXAROTENE	4	BLM
DICLOFENAC SODIUM	4	BLM
CLOTRIMAZOLE	4	BLM
FLUORESCEIN	4	BLM
OXCARBAZEPINE	4	BLM
BUMETANIDE	4	BLM
GLIPIZIDE	4	BLM
SALMETEROL XINAFOATE	4	BLM
AMIODARONE HYDROCHLORIDE	4	ATM, BLM
INDIGOTINDISULFONATE	4	BLM
TRIHEXYPHENIDYL HYDROCHLORIDE	4	BLM
RALOXIFENE HYDROCHLORIDE	4	BLM
IDARUBICIN	4	BLM
EDROPHONIUM CHLORIDE	4	BLM
PINACIDIL ANHYDROUS	4	BLM
DITHIAZANINE	4	BLM
TRIMETREXATE	4	BLM
NICARDIPINE HYDROCHLORIDE	4	BLM
PILOCARPINE HYDROCHLORIDE	4	BLM
PHENYLEPHRINE HYDROCHLORIDE	4	BLM
APRACLONIDINE HYDROCHLORIDE	4	BLM
DOXYLAMINE SUCCINATE	4	BLM
ROPINIROLE HYDROCHLORIDE	4	BLM

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	RPS20, CHEK2, BLM, ATM
B	Phased (≥1) drug, not yet approved	3	SMARCA4, EPHX1, MSH6
C	Druggable family + PDB, no drug	2	EPCAM, GNE
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	9	CDKN1B, CTNNA1, XRCC4, FAN1, NFKBIZ, CFTR-AS1, MLH1, MSH2, PMS2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MLH1	0	MSH6
PMS2	1	MSH6
CDKN1B	5	—
CTNNA1	2	—
XRCC4	1	—
FAN1	0	—
NFKBIZ	0	—
EPCAM	1	—
GNE	1	—
CFTR-AS1	0	—
MSH2	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 14.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	14

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02206360	Not specified	ACTIVE_NOT_RECRUITING	Pancreatic Cancer Early Detection Program
NCT03303833	Not specified	RECRUITING	The GEOLynch Cohort Study
NCT06708429	Not specified	RECRUITING	Lynch Syndrome X-Talk of Enteral Mucosa With Immune System
NCT06989814	Not specified	RECRUITING	Smart Measurement of Circulating Tumor DNA
NCT00141466	Not specified	UNKNOWN	Implementation of a New Strategy to Identify HNPCC Patients
NCT00262171	Not specified	UNKNOWN	Hereditary Nonpolyposis Colorectal Cancer in Taiwan-Related Genetic Study and Clinical Applications
NCT00341575	Not specified	COMPLETED	Psychosocial Aspects of Genetic Testing for Hereditary Nonpolyposis Colon Cancer
NCT00508573	Not specified	COMPLETED	Registry for Women Who Are At Risk Or May Have Lynch Syndrome
NCT01216930	Not specified	COMPLETED	Molecular Screening for Lynch Syndrome in Southern Denmark
NCT01646112	Not specified	COMPLETED	Uncertain Genetic Test Results for Lynch Syndrome
NCT01823471	Not specified	COMPLETED	I-Scan For Colon Polyp Detection In HNPCC
NCT01845753	Not specified	COMPLETED	Molecular Screening for Lynch Syndrome in Denmark
NCT02198092	Not specified	COMPLETED	Preliminary Evaluation of Septin9 in Patients With Hereditary Colon Cancer Syndromes
NCT06426927	Not specified	COMPLETED	PeLear CCC: Proyecto Latino Contra Cancer Colorrectal

Cohort genes: SMARCA4, CHEK2, CDKN1B, CTNNA1, NFKBIZ, ATM, EPCAM, MLH1, MSH2, MSH6, PMS2, RPS20, BLM, XRCC4, FAN1, EPHX1, GNE, CFTR-AS1
Associated genes: PTPRJ