Muir-Torre syndrome

Summary

Muir-Torre syndrome (MONDO:0008018) is a disease caused by variants in MLH1 and MSH2, with 5 cohort genes and 1 clinical trial. The dominant Reactome pathway is Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) (4 cohort genes).

At a glance

• Causal genes: MLH1 (GenCC Definitive), MSH2 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 612
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Muir-Torre syndrome
Mondo ID	MONDO:0008018
MeSH	D055653
OMIM	158320
Orphanet	587
DOID	DOID:0050465
ICD-11	229304403
NCIT	C84905
SNOMED CT	403824007
UMLS	C1321489
MedGen	231157
GARD	0006821
MedDRA	10063042
Is cancer (heuristic)	no

Also known as: cutaneous sebaceous neoplasms and keratoacanthomas multiple with gastrointestinal and other carcinomas · MRTES · Muir-Torre syndrome · multiple keratoacanthoma, Muir-Torre type

Data availability: 612 ClinVar variants · 9 GenCC gene-disease records · 1 cell line.

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 › Muir-Torre 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, 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, PTEN hamartoma tumor syndrome, 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

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:

231 conflicting classifications of pathogenicity, 105 pathogenic, 98 uncertain significance, 56 benign/likely benign, 37 likely benign, 33 benign, 24 likely pathogenic, 16 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3779909	NC_000002.12:g.107580437_107580438del		Pathogenic	criteria provided, single submitter
3891681	NC_000003.12:g.48091287_48091298del		Pathogenic	criteria provided, single submitter
625694	GRCh37/hg19 3p22.2(chr3:37089011-37116538)	LRRFIP2	Pathogenic	criteria provided, single submitter
1329486	NM_000249.4(MLH1):c.157G>T (p.Glu53Ter)	MLH1	Pathogenic	criteria provided, single submitter
1404368	NM_000249.4(MLH1):c.816del (p.Arg273fs)	MLH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685949	NM_000249.4(MLH1):c.1972del (p.Leu658fs)	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
17099	NM_000249.4(MLH1):c.2041G>A (p.Ala681Thr)	MLH1	Pathogenic	reviewed by expert panel
1748267	NM_000249.4(MLH1):c.1204_1207dup (p.Pro403fs)	MLH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1764964	NM_000249.4(MLH1):c.887T>A (p.Leu296Ter)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1777580	NM_000249.4(MLH1):c.1667+1G>T	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1781909	NM_000249.4(MLH1):c.1882_1883del (p.Leu628fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1786014	NM_000249.4(MLH1):c.2109_2112dup (p.Pro705fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
29654	NM_000249.4(MLH1):c.793C>T (p.Arg265Cys)	MLH1	Pathogenic	reviewed by expert panel
36540	NM_000249.4(MLH1):c.1381A>T (p.Lys461Ter)	MLH1	Pathogenic	reviewed by expert panel
3779856	NM_000249.4(MLH1):c.2061del (p.Lys688fs)	MLH1	Pathogenic	criteria provided, single submitter
3779859	NM_000249.4(MLH1):c.413dup (p.Pro139fs)	MLH1	Pathogenic	criteria provided, single submitter
3779862	NM_000249.4(MLH1):c.134_135insT (p.Ser46fs)	MLH1	Pathogenic	criteria provided, single submitter
3779864	NM_000249.4(MLH1):c.546_589-58del	MLH1	Pathogenic	criteria provided, single submitter
3779867	NM_000249.4(MLH1):c.2038_2063del (p.Cys680fs)	MLH1	Pathogenic	criteria provided, single submitter
3780863	NC_000003.11:g.(?37055923)(37083822_?)del	MLH1	Pathogenic	criteria provided, single submitter
3780864	NC_000003.11:g.(?37081677)(37083822_?)del	MLH1	Pathogenic	criteria provided, single submitter
3780865	NM_000249.4(MLH1):c.1559-1_1667+1del	MLH1	Pathogenic	criteria provided, single submitter
3891677	NM_000249.4(MLH1):c.135_137delinsTACT (p.Ser46fs)	MLH1	Pathogenic	criteria provided, single submitter
405406	NM_000249.4(MLH1):c.1105dup (p.Ser369fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
421912	NM_000249.4(MLH1):c.283del (p.Ser95fs)	MLH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
42192	NM_000249.4(MLH1):c.218T>G (p.Leu73Arg)	MLH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
433852	NM_000249.4(MLH1):c.492del (p.Ala165fs)	MLH1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 68 · Orphanet: 8 · 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	Muir-Torre syndrome	19
MSH2	Strong	Autosomal dominant	Muir-Torre syndrome	17
MSH6	Moderate	Autosomal dominant	Muir-Torre syndrome	17
PMS2	Moderate	Autosomal recessive	Muir-Torre syndrome	15

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
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

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

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
MSH6	HGNC:7329	ENSG00000116062	P52701	DNA mismatch repair protein Msh6	gencc
PMS2	HGNC:9122	ENSG00000122512	P54278	Mismatch repair endonuclease PMS2	gencc
LRRFIP2	HGNC:6703	ENSG00000093167	Q9Y608	Leucine-rich repeat flightless-interacting protein 2	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).
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).
LRRFIP2	Leucine-rich repeat flightless-interacting protein 2	May function as activator of the canonical Wnt signaling pathway, in association with DVL3, upstream of CTNNB1/beta-catenin.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 5 · Druggable fraction: 0.0

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
Other/Unknown	5	1.8×	0.054

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
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
LRRFIP2	Other/Unknown	no		LRRFIP1/2

Expression context

Cohort genes with no expression data: 0.

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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	2
deltoid	1
skeletal muscle tissue of rectus abdominis	1
tibialis anterior	1
oocyte	1
secondary oocyte	1
embryo	1
ganglionic eminence	1
male germ line stem cell (sensu Vertebrata) in testis	1
prefrontal cortex	1
thymus	1
buccal mucosa cell	1
calcaneal tendon	1
tendon	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
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
LRRFIP2	286	ubiquitous	marker	buccal mucosa cell, calcaneal tendon, tendon

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MSH2	4,537
MLH1	4,435
MSH6	4,091
PMS2	2,658
LRRFIP2	941

Intra-cohort edges

A	B	Sources
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: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MSH2	P43246	30
PMS2	P54278	9
MSH6	P52701	8
MLH1	P40692	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LRRFIP2	Q9Y608	68.23

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	4	815.7×	3e-11	MLH1, MSH2, MSH6, PMS2
Mismatch Repair	3	2141.2×	5e-10	MLH1, MSH2, MSH6
Diseases of Mismatch Repair (MMR)	3	2141.2×	5e-10	MLH1, MSH2, MSH6
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	3	611.8×	3e-08	MLH1, MSH2, PMS2
Diseases of DNA repair	3	428.2×	8e-08	MLH1, MSH2, MSH6
Defective Mismatch Repair Associated With MLH1	2	2855.0×	2e-07	MLH1, PMS2
Defective Mismatch Repair Associated With MSH6	2	2855.0×	2e-07	MSH2, MSH6
Defective Mismatch Repair Associated With PMS2	2	2855.0×	2e-07	MLH1, PMS2
Defective Mismatch Repair Associated With MSH2	2	1903.3×	6e-07	MSH2, MSH6
TP53 Regulates Transcription of DNA Repair Genes	3	135.9×	1e-06	MLH1, MSH2, PMS2
DNA Repair	3	73.8×	8e-06	MLH1, MSH2, MSH6
Defective Mismatch Repair Associated With MSH3	1	1427.5×	0.001	MSH2
Transcriptional Regulation by TP53	2	31.0×	0.002	MLH1, MSH2
Disease	3	9.8×	0.003	MLH1, MSH2, MSH6
RNA Polymerase II Transcription	2	11.3×	0.016	MLH1, MSH2
Meiosis	1	71.4×	0.018	MLH1
Gene expression (Transcription)	2	8.9×	0.022	MLH1, MSH2
Reproduction	1	47.6×	0.024	MLH1
Generic Transcription Pathway	2	7.5×	0.027	MLH1, MSH2
Meiotic recombination	1	32.4×	0.032	MLH1
Cell Cycle	1	9.0×	0.107	MLH1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
somatic hypermutation of immunoglobulin genes	4	842.6×	1e-10	MLH1, MSH2, MSH6, PMS2
mismatch repair	4	518.5×	5e-10	MLH1, MSH2, MSH6, PMS2
somatic recombination of immunoglobulin gene segments	3	2527.8×	8e-10	MSH2, MSH6, PMS2
positive regulation of isotype switching to IgA isotypes	3	1685.2×	3e-09	MLH1, MSH2, PMS2
positive regulation of isotype switching to IgG isotypes	3	919.2×	2e-08	MLH1, MSH2, PMS2
isotype switching	3	505.6×	1e-07	MLH1, MSH2, MSH6
negative regulation of DNA recombination	2	449.4×	5e-05	MSH2, MSH6
determination of adult lifespan	2	172.8×	3e-04	MSH2, MSH6
intrinsic apoptotic signaling pathway in response to DNA damage	2	129.6×	5e-04	MLH1, MSH6
meiotic mismatch repair	1	3370.4×	0.001	MSH6
somatic recombination of immunoglobulin genes involved in immune response	1	3370.4×	0.001	MSH2
meiotic metaphase I homologous chromosome alignment	1	3370.4×	0.001	MLH1
meiotic spindle midzone assembly	1	1685.2×	0.002	MLH1
male meiosis chromosome segregation	1	1123.5×	0.003	MLH1
negative regulation of mitotic recombination	1	1123.5×	0.003	MLH1
female meiosis chromosome segregation	1	842.6×	0.003	MLH1
B cell mediated immunity	1	842.6×	0.003	MSH2
maintenance of DNA repeat elements	1	674.1×	0.004	MSH2
mitotic recombination	1	561.7×	0.004	MSH2
DNA repair	2	25.5×	0.005	MSH2, MSH6
response to UV-B	1	374.5×	0.005	MSH2
meiotic telomere clustering	1	374.5×	0.005	MLH1
DNA damage tolerance	1	337.0×	0.006	MSH2
oxidative phosphorylation	1	280.9×	0.007	MSH2
resolution of meiotic recombination intermediates	1	187.2×	0.009	MLH1
mitotic intra-S DNA damage checkpoint signaling	1	187.2×	0.009	MSH2
response to X-ray	1	177.4×	0.009	MSH2
nuclear-transcribed mRNA poly(A) tail shortening	1	160.5×	0.010	MLH1
spermatogenesis	2	14.1×	0.012	MLH1, MSH6
homologous chromosome pairing at meiosis	1	120.4×	0.012	MLH1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 5 evidence-associated genes (60%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MSH6	1	2
MLH1	0	0
MSH2	0	0
PMS2	0	0
LRRFIP2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	MSH6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MSH6	10	Binding:10
MSH2	9	Binding:9
PMS2	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
MOLIBRESIB	2	MSH6

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	1	MSH6
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	MLH1, MSH2, PMS2, LRRFIP2

Undrugged target profiles

4 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
MSH2	9	—
LRRFIP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07201012	Not specified	NOT_YET_RECRUITING	Determining the Prevalence of Muir-Torre Syndrome in Patients With Lynch Syndrome