Lynch syndrome 1

Summary

Lynch syndrome 1 (MONDO:0007356) is a disease caused by variants in MSH2 and MLH1, with 20 cohort genes. The dominant Reactome pathway is Diseases of DNA repair (5 cohort genes).

At a glance

• Causal genes: MSH2 (GenCC Definitive), MLH1 (GenCC Strong)
• Cohort genes: 20
• ClinVar variants: 3,082

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Lynch syndrome 1
Mondo ID	MONDO:0007356
MeSH	C537261
OMIM	120435
DOID	DOID:0070271
NCIT	C6725
UMLS	C2936783
MedGen	423615
GARD	0015052
Is cancer (heuristic)	no

Also known as: COCA1 · familial non-polyposis colon cancer type 1 · Hereditary non-polyposis colon cancer type 1 · hereditary nonpolyposis colorectal cancer type 1 · HNPCC1 · Lynch 1 syndrome · Lynch syndrome 1 · Lynch syndrome type 1 · MSH2-related Lynch syndrome

Data availability: 3,082 ClinVar variants · 15 ClinGen variant curations · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Lynch syndrome › Lynch syndrome 1

Related subtypes (4): Lynch syndrome 2, Lynch syndrome 8, Lynch syndrome 4, Lynch syndrome 5

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:

170 conflicting classifications of pathogenicity, 167 benign/likely benign, 126 pathogenic, 39 uncertain significance, 32 likely benign, 31 pathogenic/likely pathogenic, 26 likely pathogenic, 7 benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1723215	Single allele	EIF2AK1	Pathogenic	criteria provided, single submitter
1012206	NM_000249.4(MLH1):c.1003del (p.Leu335fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1332889	NM_000249.4(MLH1):c.1731+2247_1897-402del	MLH1	Pathogenic	no assertion criteria provided
1344897	NM_000249.4(MLH1):c.55_63delinsT (p.Ile19fs)	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
17094	NM_000249.4(MLH1):c.350C>T (p.Thr117Met)	MLH1	Pathogenic	reviewed by expert panel
1012207	NM_000251.3(MSH2):c.1763_1764del (p.Tyr588fs)	MSH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048814	NM_000251.3(MSH2):c.459del (p.Ala154fs)	MSH2	Pathogenic	criteria provided, single submitter
1049291	NM_000251.3(MSH2):c.1163dup (p.Asn388fs)	MSH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1049378	NM_000251.3(MSH2):c.2005+2T>G	MSH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1050723	NM_000251.3(MSH2):c.999dup (p.Lys334Ter)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1050772	NM_000251.3(MSH2):c.1387-2del	MSH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066298	NM_000251.3(MSH2):c.2006-7_2022del	MSH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071117	NM_000251.3(MSH2):c.1270del (p.His424fs)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1071840	NM_000251.3(MSH2):c.1487del (p.Thr495_Leu496insTer)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1072133	NM_000251.3(MSH2):c.1511-2A>C	MSH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072627	NM_000251.3(MSH2):c.1698del (p.Asn566fs)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1072896	NM_000251.3(MSH2):c.2386_2396del (p.Thr796fs)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1073269	NM_000251.3(MSH2):c.1511del (p.Gly504Alafs)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1073675	NM_000251.3(MSH2):c.1613del (p.Asn538fs)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1075054	NM_000251.3(MSH2):c.1222_1223insTT (p.Tyr408fs)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1075095	NM_000251.3(MSH2):c.2445T>A (p.Tyr815Ter)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1076317	NM_000251.3(MSH2):c.2361del (p.Thr788fs)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1076832	NM_000251.3(MSH2):c.377del (p.Gly126fs)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1098797	NM_000251.3(MSH2):c.1393_1420del (p.Asn465fs)	MSH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1203214	NM_000251.3(MSH2):c.1876G>T (p.Glu626Ter)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1207453	NM_000251.3(MSH2):c.478_479del (p.Gln160fs)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
127635	NM_000251.3(MSH2):c.1744del (p.Val582fs)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
127650	NM_000251.3(MSH2):c.686_687del (p.Lys229fs)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 36 · Orphanet: 47 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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
MLH1	Definitive	Autosomal dominant	Lynch syndrome 2	19
MSH2	Definitive	Autosomal dominant	Lynch syndrome 1	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
BRCA1	Orphanet:1331	Familial prostate cancer
BRCA1	Orphanet:1333	Familial pancreatic carcinoma
BRCA1	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRCA1	Orphanet:168829	Primary peritoneal carcinoma
BRCA1	Orphanet:227535	Hereditary breast cancer
BRCA1	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
BRCA1	Orphanet:694963	Inflammatory breast cancer
BRCA1	Orphanet:70567	Cholangiocarcinoma
BRCA1	Orphanet:84	Fanconi anemia
EPCAM	Orphanet:144	Lynch syndrome
EPCAM	Orphanet:92050	Congenital tufting enteropathy
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
NPHP4	Orphanet:3156	Senior-Loken syndrome
NPHP4	Orphanet:93592	Juvenile nephronophthisis
PALB2	Orphanet:1333	Familial pancreatic carcinoma
PALB2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
PALB2	Orphanet:178	Chordoma
PALB2	Orphanet:227535	Hereditary breast cancer
PALB2	Orphanet:84	Fanconi anemia
MSH6	Orphanet:144	Lynch syndrome
MSH6	Orphanet:252202	Constitutional mismatch repair deficiency syndrome
MUTYH	Orphanet:247798	MUTYH-related polyposis
MUTYH	Orphanet:440437	Familial colorectal cancer Type X
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
PCK1	Orphanet:2880	Phosphoenolpyruvate carboxykinase deficiency
PMS1	Orphanet:144	Lynch syndrome
PMS2	Orphanet:144	Lynch syndrome
PMS2	Orphanet:252202	Constitutional mismatch repair deficiency syndrome
CTSA	Orphanet:351	Galactosialidosis
CTSA	Orphanet:575553	Cathepsin A-related arteriopathy-strokes-leukoencephalopathy
RAD51D	Orphanet:1331	Familial prostate cancer
RAD51D	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome

Cohort genes → proteins

20 cohort genes, 19 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	20

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MLH1	HGNC:7127	ENSG00000076242	P40692	DNA mismatch repair protein Mlh1	gencc,clinvar
MSH2	HGNC:7325	ENSG00000095002	P43246	DNA mismatch repair protein Msh2	gencc,clinvar
BCYRN1	HGNC:1022	ENSG00000236824		brain cytoplasmic RNA 1	clinvar
BRCA1	HGNC:1100	ENSG00000012048	P38398	Breast cancer type 1 susceptibility protein	clinvar
EPCAM	HGNC:11529	ENSG00000119888	P16422	Epithelial cell adhesion molecule	clinvar
CHEK2	HGNC:16627	ENSG00000183765	O96017	Serine/threonine-protein kinase Chk2	clinvar
NISCH	HGNC:18006	ENSG00000010322	Q9Y2I1	Nischarin	clinvar
NPHP4	HGNC:19104	ENSG00000131697	O75161	Nephrocystin-4	clinvar
EIF2AK1	HGNC:24921	ENSG00000086232	Q9BQI3	Eukaryotic translation initiation factor 2-alpha kinase 1	clinvar
PALB2	HGNC:26144	ENSG00000083093	Q86YC2	Partner and localizer of BRCA2	clinvar
KCNK12	HGNC:6274	ENSG00000184261	Q9HB15	Potassium channel subfamily K member 12	clinvar
MLH3	HGNC:7128	ENSG00000119684	Q9UHC1	DNA mismatch repair protein Mlh3	clinvar
MSH6	HGNC:7329	ENSG00000116062	P52701	DNA mismatch repair protein Msh6	clinvar
MUTYH	HGNC:7527	ENSG00000132781	Q9UIF7	Adenine DNA glycosylase	clinvar
ATM	HGNC:795	ENSG00000149311	Q13315	Serine-protein kinase ATM	clinvar
PCK1	HGNC:8724	ENSG00000124253	P35558	Phosphoenolpyruvate carboxykinase, cytosolic [GTP]	clinvar
PMS1	HGNC:9121	ENSG00000064933	P54277	PMS1 protein homolog 1	clinvar
PMS2	HGNC:9122	ENSG00000122512	P54278	Mismatch repair endonuclease PMS2	clinvar
CTSA	HGNC:9251	ENSG00000064601	P10619	Lysosomal protective protein	clinvar
RAD51D	HGNC:9823	ENSG00000185379	O75771	DNA repair protein RAD51 homolog 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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).
BRCA1	Breast cancer type 1 susceptibility protein	E3 ubiquitin-protein ligase that specifically mediates the formation of ‘Lys-6’-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage.
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…
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.
NISCH	Nischarin	Acts either as the functional imidazoline-1 receptor (I1R) candidate or as a membrane-associated mediator of the I1R signaling.
NPHP4	Nephrocystin-4	Involved in the organization of apical junctions; the function is proposed to implicate a NPHP1-4-8 module.
EIF2AK1	Eukaryotic translation initiation factor 2-alpha kinase 1	Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress conditions.
PALB2	Partner and localizer of BRCA2	Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks.
KCNK12	Potassium channel subfamily K member 12	K(+) channel subunit that may homo- and heterodimerize to form functional channels with distinct regulatory and gating properties.
MLH3	DNA mismatch repair protein Mlh3	Probably involved in the repair of mismatches in DNA.
MSH6	DNA mismatch repair protein Msh6	Component of the post-replicative DNA mismatch repair system (MMR).
MUTYH	Adenine DNA glycosylase	Involved in oxidative DNA damage repair.
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.
PCK1	Phosphoenolpyruvate carboxykinase, cytosolic [GTP]	Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis.
PMS1	PMS1 protein homolog 1	Probably involved in the repair of mismatches in DNA.
PMS2	Mismatch repair endonuclease PMS2	Component of the post-replicative DNA mismatch repair system (MMR).
CTSA	Lysosomal protective protein	Protective protein appears to be essential for both the activity of beta-galactosidase and neuraminidase, it associates with these enzymes and exerts a protective function necessary for their stability and activity.
RAD51D	DNA repair protein RAD51 homolog 4	Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents.

Protein-family classification

Druggable: 7 · Difficult: 2 · Unknown: 11 · Druggable fraction: 0.35

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	4	5.5×	0.036
Ion channel	1	5.6×	0.577
Protease	1	1.8×	0.924
Other/Unknown	11	1.0×	0.924
Scaffold/PPI	1	0.9×	0.924
Enzyme (other)	1	0.6×	0.924
Transcription factor	1	0.4×	0.924

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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
BCYRN1	Other/Unknown	no
BRCA1	Transcription factor	no	2.3.2.27	BRCT_dom, Znf_RING, BRCA1
EPCAM	Enzyme (other)	yes	2.4.1.37	Thyroglobulin_1, Thyroglobulin_1_sf, EpCAM_N
CHEK2	Kinase	yes	2.7.11.1	FHA_dom, Prot_kinase_dom, Ser/Thr_kinase_AS
NISCH	Other/Unknown	no		Leu-rich_rpt, PX_dom, LRR_dom_sf
NPHP4	Other/Unknown	no		NPHP4, Ig_NPHP4_4th, Ig_NPHP4_3rd
EIF2AK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
PALB2	Scaffold/PPI	no		WD40/YVTN_repeat-like_dom_sf, PALB2_WD40, WD40_repeat_dom_sf
KCNK12	Ion channel	yes		2pore_dom_K_chnl, 2pore_dom_K_chnl_THIK, K_chnl_dom
MLH3	Other/Unknown	no		MutL/Mlh/PMS, DNA_mismatch_S5_2-like, Ribsml_uS5_D2-typ_fold_subgr
MSH6	Other/Unknown	no		PWWP_dom, DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS-lik_N
MUTYH	Other/Unknown	no		NUDIX_hydrolase_dom, HhH_motif, HhH-GPD_domain
ATM	Kinase	yes	2.7.11.1	PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
PCK1	Kinase	yes	4.1.1.32	PEP_carboxykinase_GTP, PEP_carboxykinase_N, PEP_carboxykinase_C
PMS1	Other/Unknown	no		MutL/Mlh/PMS, HMG_box_dom, DNA_mismatch_S5_2-like
PMS2	Other/Unknown	no		MutL/Mlh/PMS, DNA_mismatch_S5_2-like, Ribsml_uS5_D2-typ_fold_subgr
CTSA	Protease	yes	3.4.16.5	Peptidase_S10, Ser_caboxypep_ser_AS, AB_hydrolase_fold
RAD51D	Other/Unknown	no		AAA+_ATPase, Rad51_C, DNA_recomb/repair_RecA-like

Expression context

Cohort genes with no expression data: 0.

18 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)	20
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	3
ventricular zone	3
male germ line stem cell (sensu Vertebrata) in testis	3
secondary oocyte	2
primordial germ cell in gonad	2
jejunal mucosa	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2
monocyte	2
mononuclear cell	2
male germ cell	2
sperm	2
deltoid	1
skeletal muscle tissue of rectus abdominis	1
tibialis anterior	1
primary visual cortex	1
superior frontal gyrus	1
temporal lobe	1
colonic mucosa	1
mucosa of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MLH1	296	ubiquitous	marker	tibialis anterior, skeletal muscle tissue of rectus abdominis, deltoid
MSH2	278	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone
BCYRN1	133		marker	primary visual cortex, superior frontal gyrus, temporal lobe
BRCA1	208	ubiquitous	marker	ventricular zone, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
EPCAM	253	broad	marker	jejunal mucosa, colonic mucosa, mucosa of sigmoid colon
CHEK2	183	ubiquitous	marker	primordial germ cell in gonad, lower esophagus mucosa, male germ line stem cell (sensu Vertebrata) in testis
NISCH	293	ubiquitous	marker	middle temporal gyrus, right hemisphere of cerebellum, cerebellar hemisphere
NPHP4	165	ubiquitous	marker	right uterine tube, adenohypophysis, right lobe of thyroid gland
EIF2AK1	289	ubiquitous	marker	trabecular bone tissue, monocyte, mononuclear cell
PALB2	232	ubiquitous	yes	secondary oocyte, buccal mucosa cell, oocyte
KCNK12	106	broad	marker	olfactory bulb, trigeminal ganglion, dorsal root ganglion
MLH3	270	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
MSH6	293	ubiquitous	marker	ventricular zone, embryo, ganglionic eminence
MUTYH	134	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
ATM	286	ubiquitous	marker	calcaneal tendon, colonic epithelium, corpus callosum
PCK1	215	tissue_specific	marker	jejunal mucosa, adult organism, right lobe of liver
PMS1	286	ubiquitous	marker	sperm, male germ cell, left testis
PMS2	143	ubiquitous	marker	thymus, prefrontal cortex, male germ line stem cell (sensu Vertebrata) in testis
CTSA	297	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland
RAD51D	187	ubiquitous	yes	sperm, male germ cell, oocyte

Protein interactions among cohort

Intra-cohort edges: 44.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BRCA1	9,064
ATM	7,383
PALB2	5,641
CHEK2	4,795
MSH2	4,537
MLH1	4,435
MSH6	4,091
EPCAM	3,359
RAD51D	3,089
CTSA	2,964

Intra-cohort edges

A	B	Sources
ATM	BRCA1	string_interaction
ATM	CHEK2	string_interaction
ATM	MLH1	string_interaction
ATM	MSH2	string_interaction
ATM	MSH6	string_interaction
ATM	PMS1	string_interaction
ATM	RAD51D	string_interaction
BRCA1	CHEK2	string_interaction
BRCA1	MLH1	string_interaction
BRCA1	MSH2	string_interaction
BRCA1	MSH6	string_interaction
BRCA1	PALB2	biogrid_interaction, intact, string_interaction
BRCA1	PMS1	string_interaction
BRCA1	PMS2	string_interaction
BRCA1	RAD51D	string_interaction
CHEK2	MSH6	string_interaction
CHEK2	PALB2	string_interaction
CHEK2	RAD51D	string_interaction
EPCAM	MLH1	string_interaction
EPCAM	MSH2	string_interaction
EPCAM	MSH6	string_interaction
EPCAM	PMS1	string_interaction
EPCAM	PMS2	string_interaction
KCNK12	MSH2	string_interaction
MLH1	MLH3	biogrid_interaction, intact
MLH1	MSH2	string_interaction
MLH1	MSH6	string_interaction
MLH1	MUTYH	string_interaction
MLH1	PMS1	biogrid_interaction, intact, string_interaction
MLH1	PMS2	biogrid_interaction, intact, string_interaction
MLH1	RAD51D	string_interaction
MSH2	MSH6	biogrid_interaction, intact, string_interaction
MSH2	MUTYH	intact, string_interaction
MSH2	PMS1	string_interaction
MSH2	PMS2	string_interaction
MSH2	RAD51D	string_interaction
MSH6	MUTYH	string_interaction
MSH6	PMS1	string_interaction
MSH6	PMS2	string_interaction
MSH6	RAD51D	string_interaction
MUTYH	PMS1	string_interaction
MUTYH	PMS2	string_interaction
PALB2	RAD51D	string_interaction
PMS1	PMS2	string_interaction

Structural data

PDB: 15 · AlphaFold-only: 4 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHEK2	O96017	38
BRCA1	P38398	33
MSH2	P43246	30
RAD51D	O75771	17
ATM	Q13315	14
CTSA	P10619	12
PMS2	P54278	9
MSH6	P52701	8
MLH1	P40692	7
PCK1	P35558	7
PALB2	Q86YC2	4
MUTYH	Q9UIF7	3
EPCAM	P16422	2
NISCH	Q9Y2I1	2
PMS1	P54277	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KCNK12	Q9HB15	73.40
NPHP4	O75161	72.44
EIF2AK1	Q9BQI3	64.31
MLH3	Q9UHC1	56.14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 122. Enrichment computed across 20 evidence-associated genes (18 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 18 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	158.6×	1e-08	MLH1, MSH2, BRCA1, MSH6, ATM
TP53 Regulates Transcription of DNA Repair Genes	6	60.4×	2e-08	MLH1, MSH2, BRCA1, ATM, PMS2, RAD51D
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	4	181.3×	2e-07	MLH1, MSH2, MSH6, PMS2
Mismatch Repair	3	475.8×	3e-07	MLH1, MSH2, MSH6
Diseases of Mismatch Repair (MMR)	3	475.8×	3e-07	MLH1, MSH2, MSH6
Impaired BRCA2 binding to PALB2	4	101.5×	1e-06	BRCA1, PALB2, ATM, RAD51D
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	4	94.0×	1e-06	BRCA1, PALB2, ATM, RAD51D
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	4	94.0×	1e-06	BRCA1, PALB2, ATM, RAD51D
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	4	94.0×	1e-06	BRCA1, PALB2, ATM, RAD51D
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	4	87.5×	1e-06	BRCA1, PALB2, ATM, RAD51D
Homologous DNA Pairing and Strand Exchange	4	84.6×	1e-06	BRCA1, PALB2, ATM, RAD51D
Resolution of D-loop Structures through Holliday Junction Intermediates	4	66.8×	3e-06	BRCA1, PALB2, ATM, RAD51D
Meiosis	4	63.4×	4e-06	MLH1, BRCA1, MLH3, ATM
DNA Repair	5	27.4×	7e-06	MLH1, MSH2, BRCA1, MSH6, ATM
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	3	135.9×	1e-05	MLH1, MSH2, PMS2
Reproduction	4	42.3×	1e-05	MLH1, BRCA1, MLH3, ATM
HDR through Homologous Recombination (HRR)	4	42.3×	1e-05	BRCA1, PALB2, ATM, RAD51D
Defective Mismatch Repair Associated With MLH1	2	634.4×	1e-05	MLH1, PMS2
Defective Mismatch Repair Associated With MSH6	2	634.4×	1e-05	MSH2, MSH6
Defective Mismatch Repair Associated With PMS2	2	634.4×	1e-05	MLH1, PMS2
Defective Mismatch Repair Associated With MSH2	2	423.0×	4e-05	MSH2, MSH6
Meiotic recombination	4	28.8×	5e-05	MLH1, BRCA1, MLH3, ATM
Presynaptic phase of homologous DNA pairing and strand exchange	3	45.3×	2e-04	BRCA1, ATM, RAD51D
Defective homologous recombination repair (HRR) due to PALB2 loss of function	2	105.7×	8e-04	BRCA1, ATM
Transcriptional Regulation by TP53	4	13.8×	8e-04	MLH1, MSH2, BRCA1, ATM
Diseases of DNA Double-Strand Break Repair	2	90.6×	1e-03	BRCA1, ATM
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	2	90.6×	1e-03	BRCA1, ATM
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	3	24.4×	0.001	BRCA1, CHEK2, ATM
Stabilization of p53	2	84.6×	0.001	CHEK2, ATM
Resolution of D-Loop Structures	2	70.5×	0.001	BRCA1, 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 19 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mismatch repair	7	238.8×	1e-13	MLH1, MSH2, MLH3, MSH6, MUTYH, PMS1, PMS2
somatic hypermutation of immunoglobulin genes	4	221.7×	2e-07	MLH1, MSH2, MSH6, PMS2
intrinsic apoptotic signaling pathway in response to DNA damage	5	85.3×	2e-07	MLH1, BRCA1, CHEK2, MSH6, ATM
somatic recombination of immunoglobulin gene segments	3	665.2×	3e-07	MSH2, MSH6, PMS2
positive regulation of isotype switching to IgA isotypes	3	443.5×	1e-06	MLH1, MSH2, PMS2
positive regulation of isotype switching to IgG isotypes	3	241.9×	7e-06	MLH1, MSH2, PMS2
isotype switching	3	133.0×	4e-05	MLH1, MSH2, MSH6
double-strand break repair	4	42.7×	6e-05	MSH2, BRCA1, CHEK2, ATM
reciprocal meiotic recombination	3	88.7×	1e-04	MLH3, ATM, RAD51D
double-strand break repair via homologous recombination	4	32.9×	1e-04	BRCA1, PALB2, ATM, RAD51D
DNA repair	5	16.8×	2e-04	MSH2, BRCA1, MSH6, MUTYH, RAD51D
determination of adult lifespan	3	68.2×	2e-04	MSH2, MSH6, ATM
meiotic telomere clustering	2	197.1×	7e-04	MLH1, ATM
DNA damage tolerance	2	177.4×	9e-04	MSH2, BRCA1
negative regulation of DNA recombination	2	118.3×	0.002	MSH2, MSH6
regulation of autophagosome assembly	2	118.3×	0.002	CHEK2, ATM
replicative senescence	2	104.3×	0.002	CHEK2, ATM
mitotic intra-S DNA damage checkpoint signaling	2	98.5×	0.002	MSH2, CHEK2
cellular response to stress	2	88.7×	0.003	CHEK2, ATM
signal transduction in response to DNA damage	2	84.5×	0.003	CHEK2, ATM
protein autophosphorylation	3	22.9×	0.003	CHEK2, EIF2AK1, ATM
cellular response to gamma radiation	2	63.4×	0.005	CHEK2, ATM
male meiotic nuclear division	2	57.2×	0.005	MLH3, ATM
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	2	52.2×	0.006	MSH2, CHEK2
mitotic G2 DNA damage checkpoint signaling	2	46.7×	0.007	BRCA1, ATM
meiotic mismatch repair	1	887.0×	0.007	MSH6
somatic recombination of immunoglobulin genes involved in immune response	1	887.0×	0.007	MSH2
meiotic metaphase I homologous chromosome alignment	1	887.0×	0.007	MLH1
negative regulation of translational initiation by iron	1	887.0×	0.007	EIF2AK1
negative regulation of hemoglobin biosynthetic process	1	887.0×	0.007	EIF2AK1

Therapeutics

Drug target analysis

Approved (phase 4): 6 · Phase ≥3: 6 · Phased (≥1): 7 · Undrugged: 13

Druggability breadth: 12 of 20 evidence-associated genes (60%) 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
BRCA1	RIBOFLAVIN
CHEK2	NERATINIB
NISCH	TIZANIDINE
EIF2AK1	FEDRATINIB
ATM	AMIODARONE HYDROCHLORIDE
CTSA	ISOFLUROPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATM	35	4
CHEK2	30	4
EIF2AK1	17	4
NISCH	15	4
BRCA1	12	4
CTSA	2	4
MSH6	1	2
MLH1	0	0
MSH2	0	0
BCYRN1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
RIBOFLAVIN	4	BRCA1
DAUNORUBICIN HYDROCHLORIDE	4	BRCA1
TOPOTECAN HYDROCHLORIDE	4	BRCA1
DAUNORUBICIN	4	BRCA1
DOXORUBICIN HYDROCHLORIDE	4	BRCA1
MESALAMINE	4	BRCA1
DIPYRIDAMOLE	4	ATM, BRCA1
NERATINIB	4	CHEK2
BOSUTINIB	4	CHEK2, EIF2AK1
BRIGATINIB	4	CHEK2
SUNITINIB	4	CHEK2
GEFITINIB	4	CHEK2
TIZANIDINE	4	NISCH
CLONIDINE	4	NISCH
MOXONIDINE	4	NISCH
RILMENIDINE	4	NISCH
GUANABENZ	4	NISCH
PHENTOLAMINE	4	NISCH
NAPHAZOLINE	4	NISCH
OXYMETAZOLINE	4	NISCH
GUANFACINE	4	NISCH
FEDRATINIB	4	EIF2AK1
DABRAFENIB	4	EIF2AK1
BARICITINIB	4	EIF2AK1
ABEMACICLIB	4	EIF2AK1
MIDOSTAURIN	4	EIF2AK1
AMIODARONE HYDROCHLORIDE	4	ATM
FURAZOLIDONE	4	ATM
ESTRADIOL ACETATE	4	ATM
NAFTIFINE HYDROCHLORIDE	4	ATM

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
EIF2AK1	124	Binding:124
NISCH	38	Binding:38
CTSA	19	Binding:13, ADMET:6
BRCA1	13	Binding:9, Functional:4
MSH6	10	Binding:10
MSH2	9	Binding:9
PCK1	2	Binding:2
EPCAM	1	Binding:1
MUTYH	1	Functional:1
PMS2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRCA1	2.3.2.27	RING-type E3 ubiquitin transferase
EPCAM	2.4.1.37, 2.4.1.40	fucosylgalactoside 3-alpha-galactosyltransferase, glycoprotein-fucosylgalactoside alpha-N-acetylgalactosaminyltransferase
CHEK2	2.7.11.1	non-specific serine/threonine protein kinase
ATM	2.7.11.1	non-specific serine/threonine protein kinase
PCK1	4.1.1.32	phosphoenolpyruvate carboxykinase (GTP)
CTSA	3.4.16.5	carboxypeptidase C

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CHEK2	690
EIF2AK1	124
ATM	240

Pharmacogenomics

Cohort genes with a PharmGKB record: 20; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
RIBOFLAVIN	4	BRCA1
DAUNORUBICIN HYDROCHLORIDE	4	BRCA1
TOPOTECAN HYDROCHLORIDE	4	BRCA1
DAUNORUBICIN	4	BRCA1
DOXORUBICIN HYDROCHLORIDE	4	BRCA1
MESALAMINE	4	BRCA1
DIPYRIDAMOLE	4	ATM, BRCA1
NERATINIB	4	CHEK2
BOSUTINIB	4	CHEK2, EIF2AK1
BRIGATINIB	4	CHEK2
SUNITINIB	4	CHEK2
GEFITINIB	4	CHEK2
TIZANIDINE	4	NISCH
CLONIDINE	4	NISCH
MOXONIDINE	4	NISCH
RILMENIDINE	4	NISCH
GUANABENZ	4	NISCH
PHENTOLAMINE	4	NISCH
NAPHAZOLINE	4	NISCH
OXYMETAZOLINE	4	NISCH
GUANFACINE	4	NISCH
FEDRATINIB	4	EIF2AK1
DABRAFENIB	4	EIF2AK1
BARICITINIB	4	EIF2AK1
ABEMACICLIB	4	EIF2AK1
MIDOSTAURIN	4	EIF2AK1
AMIODARONE HYDROCHLORIDE	4	ATM
FURAZOLIDONE	4	ATM
ESTRADIOL ACETATE	4	ATM
NAFTIFINE HYDROCHLORIDE	4	ATM

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	6	BRCA1, CHEK2, NISCH, EIF2AK1, ATM, CTSA
B	Phased (≥1) drug, not yet approved	1	MSH6
C	Druggable family + PDB, no drug	2	EPCAM, PCK1
D	Druggable family + AlphaFold only, no drug	1	KCNK12
E	Difficult family or no structure, no drug	10	MLH1, MSH2, BCYRN1, NPHP4, PALB2, MLH3, MUTYH, PMS1, PMS2, RAD51D

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MLH1	0	MSH6
PALB2	0	BRCA1
MUTYH	1	MSH6
PMS1	0	MSH6
PMS2	1	MSH6
RAD51D	0	BRCA1
MSH2	9	—
BCYRN1	0	—
EPCAM	1	—
NPHP4	0	—
KCNK12	0	—
MLH3	0	—
PCK1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.