Mismatch repair cancer syndrome 1
diseaseOn this page
Also known as brain tumor-polyposis syndromebrain tumor-polyposis syndrome 1BTP1 syndromeCNS tumors with familial polyposis of the colonCNS tumours with familial polyposis of the colonglioma-polyposis syndromemalignant tumors of the central nervous system associated with familial polyposis of the colonmalignant tumours of the central nervous system associated with familial polyposis of the colonmismatch repair cancer syndromeMLH1-related constitutional mismatch repair deficiency syndromeMMRCSMMRCS1Turcot Syndrome
Summary
Mismatch repair cancer syndrome 1 (MONDO:0010159) is a cancer caused by variants in MLH1, MSH2, MSH6, and 1 other genes, with 4 cohort genes (4 CIViC-evidence somatic drivers; 355 ClinVar predisposition records) and 1 clinical trial. The dominant Reactome pathway is Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) (4 cohort genes).
At a glance
- Classification: Cancer
- Causal genes: MLH1 (GenCC Definitive), MSH2 (GenCC Definitive), MSH6 (GenCC Definitive), PMS2 (GenCC Definitive)
- Cohort genes: 4
- ClinVar variants: 355
- Clinical trials: 1
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | mismatch repair cancer syndrome 1 |
| Mondo ID | MONDO:0010159 |
| MeSH | C536928 |
| OMIM | 276300 |
| SNOMED CT | 61665008 |
| UMLS | C5399763 |
| MedGen | 1748029 |
| GARD | 0000420 |
| NORD | 1805 |
| Is cancer (heuristic) | yes |
Also known as: brain tumor-polyposis syndrome · brain tumor-polyposis syndrome 1 · BTP1 syndrome · CNS tumors with familial polyposis of the colon · CNS tumours with familial polyposis of the colon · glioma-polyposis syndrome · malignant tumors of the central nervous system associated with familial polyposis of the colon · malignant tumours of the central nervous system associated with familial polyposis of the colon · mismatch repair cancer syndrome · mismatch repair cancer syndrome 1 · MLH1-related constitutional mismatch repair deficiency syndrome · MMRCS · MMRCS1 · Turcot Syndrome
Data availability: 355 ClinVar variants · 11 GenCC gene-disease records · 2 cell lines.
Disease family
Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › mismatch repair cancer syndrome 1
Related subtypes (116): mosaic variegated aneuploidy syndrome, tuberous sclerosis, hereditary breast ovarian cancer syndrome, hereditary multiple osteochondromas, nevoid basal cell carcinoma syndrome, leukemia, chronic lymphocytic, susceptibility to, 2, blue rubber bleb nevus, cherubism, Beckwith-Wiedemann syndrome, multiple self-healing squamous epithelioma, erythroleukemia, familial, susceptibility to, goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, hyperparathyroidism 2 with jaw tumors, Kaposi sarcoma, susceptibility to, hereditary leiomyomatosis and renal cell cancer, susceptibility to uveal melanoma, melanoma and neural system tumor syndrome, nasopharyngeal carcinoma, susceptibility to, 2, WAGR syndrome, neuroblastoma, susceptibility to, 1, Rothmund-Thomson syndrome, Wiskott-Aldrich syndrome, N syndrome, hereditary thrombocytopenia and hematologic cancer predisposition syndrome, prostate cancer/brain cancer susceptibility, Brooke-Spiegler syndrome, pancreatic cancer, susceptibility to, 1, Carney-Stratakis syndrome, nasopharyngeal carcinoma, susceptibility to, 1, ovarian cancer, susceptibility to, 1, colorectal cancer, susceptibility to, 1, lung cancer susceptibility 1, leukemia, chronic lymphocytic, susceptibility to, 1, Kostmann syndrome, colorectal cancer, susceptibility to, 2, colorectal cancer, susceptibility to, 3, colorectal cancer, susceptibility to, 5, colorectal cancer, susceptibility to, 6, colorectal cancer, susceptibility to, 7, leukemia, chronic lymphocytic, susceptibility to, 3, leukemia, chronic lymphocytic, susceptibility to, 4, leukemia, chronic lymphocytic, susceptibility to, 5, lung cancer susceptibility 3, colorectal cancer, susceptibility to, 8, colorectal cancer, susceptibility to, 9, colorectal cancer, susceptibility to, 10, colorectal cancer, susceptibility to, 11, lung cancer susceptibility 4, neuroblastoma, susceptibility to, 3, neuroblastoma, susceptibility to, 4, neuroblastoma, susceptibility to, 5, neuroblastoma, susceptibility to, 6, leukemia, acute lymphocytic, susceptibility to, 1, leukemia, acute lymphocytic, susceptibility to, 2, lung cancer susceptibility 5, BAP1-related tumor predisposition syndrome, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Maffucci syndrome, basal cell carcinoma, susceptibility to, 7, colorectal cancer, susceptibility to, 12, leukemia, acute lymphoblastic, susceptibility to, 3, cholangiocarcinoma, susceptibility to, progeroid features-hepatocellular carcinoma predisposition syndrome, neuroblastoma, susceptibility to, 7, DDX41-related hematologic malignancy predisposition syndrome, nasopharyngeal carcinoma, susceptibility to, 3, familial isolated hyperparathyroidism, intestinal polyposis syndrome, dyskeratosis congenita, familial rhabdoid tumor, multiple endocrine neoplasia, hereditary pheochromocytoma-paraganglioma, PTEN hamartoma tumor syndrome, familial multiple fibrofolliculoma, hereditary retinoblastoma, familial atypical multiple mole melanoma syndrome, hereditary nonpolyposis colon cancer, Li-Fraumeni syndrome, Cobb syndrome, neurofibromatosis, susceptibility to familial cutaneous melanoma, pancreatic cancer, susceptibility to, 5, leukemia, acute myeloid, susceptibility to, diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, glioma susceptibility, hemangioma, capillary infantile, susceptibility to, CDH1-related diffuse gastric and lobular breast cancer syndrome, NTHL1-deficiency tumor predisposition syndrome, SAMD9-related spectrum and myeloid neoplasm risk, neuroblastoma, susceptibility to, 2, BARD1-related cancer predisposition, BRCA1-related cancer predisposition, BRCA2-related cancer predisposition, ATM-related cancer predisposition, CHEK2-related cancer predisposition, PALB2-related cancer predisposition, RAD51C-related cancer predisposition, RAD51D-related cancer predisposition, Li-fraumeni-like syndrome, breast cancer, familial, susceptibility to, 1, breast cancer, familial, susceptibility to, 2, breast cancer, familial, susceptibility to, 3, colorectal cancer, susceptibility to, 4, colorectal cancer, susceptibility to, on chromosome 15, ovarian cancer, familial, susceptibility to, 1, ovarian cancer, familial, susceptibility to, 2, ovarian cancer, familial, susceptibility to, 3, inherited hematologic cancer-predisposing syndrome, mosaic neurofibromatosis/schwannomatosis, tumor predisposition syndrome 2, prostate cancer, hereditary, X-linked 3, follicular lymphoma, susceptibility to, GPR161-related medulloblastoma predisposition, SAMD9L-related spectrum and myeloid neoplasm risk, HAVCR2-related cancer predisposition, EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition
Genetics & variants
GWAS landscape
No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.
Variant details and genetic-evidence tiers
ClinVar germline variants
355 retrieved; paginated sample, class counts are floors:
154 conflicting classifications of pathogenicity, 63 pathogenic, 62 uncertain significance, 17 pathogenic/likely pathogenic, 16 benign/likely benign, 15 likely pathogenic, 14 benign, 14 likely benign
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 3891681 | NC_000003.12:g.48091287_48091298del | Pathogenic | criteria provided, single submitter | |
| 1404368 | NM_000249.4(MLH1):c.816del (p.Arg273fs) | MLH1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 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 |
| 17088 | NM_000249.4(MLH1):c.199G>T (p.Gly67Trp) | MLH1 | Pathogenic | reviewed by expert panel |
| 17091 | MLH1, EX16DEL | MLH1 | Pathogenic | no assertion criteria provided |
| 17094 | NM_000249.4(MLH1):c.350C>T (p.Thr117Met) | MLH1 | Pathogenic | reviewed by expert panel |
| 17097 | NM_000249.4(MLH1):c.1942C>T (p.Pro648Ser) | MLH1 | Pathogenic | reviewed by expert panel |
| 17099 | NM_000249.4(MLH1):c.2041G>A (p.Ala681Thr) | MLH1 | Pathogenic | reviewed by expert panel |
| 17105 | NM_000249.4(MLH1):c.104_105delinsAC (p.Met35Asn) | 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 |
| 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 |
| 3779867 | NM_000249.4(MLH1):c.2038_2063del (p.Cys680fs) | 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 |
| 42192 | NM_000249.4(MLH1):c.218T>G (p.Leu73Arg) | MLH1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 449776 | NM_000249.4(MLH1):c.1667G>A (p.Ser556Asn) | MLH1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 580133 | NM_000249.4(MLH1):c.885-1G>A | MLH1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 642710 | NM_000249.4(MLH1):c.2070C>G (p.Tyr690Ter) | MLH1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 89744 | NM_000249.4(MLH1):c.1459C>T (p.Arg487Ter) | MLH1 | Pathogenic | reviewed by expert panel |
| 89749 | NM_000249.4(MLH1):c.146T>A (p.Val49Glu) | MLH1 | Pathogenic | reviewed by expert panel |
| 89857 | NM_000249.4(MLH1):c.1731G>A (p.Ser577=) | MLH1 | Pathogenic | reviewed by expert panel |
| 89888 | NM_000249.4(MLH1):c.1783_1784del (p.Ser595fs) | MLH1 | Pathogenic | reviewed by expert panel |
| 89935 | NM_000249.4(MLH1):c.18_34del (p.Val7fs) | MLH1 | Pathogenic | reviewed by expert panel |
| 89994 | NM_000249.4(MLH1):c.1A>G (p.Met1Val) | MLH1 | Pathogenic | reviewed by expert panel |
| 90011 | NM_000249.4(MLH1):c.2042C>T (p.Ala681Val) | MLH1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 68 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0
Somatic driver evidence (intOGen + CIViC, cohort fanout)
| Gene | intOGen role | Cancer types | CIViC |
|---|---|---|---|
| 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 |
|---|---|---|---|---|
| MLH1 | Definitive | Autosomal recessive | mismatch repair cancer syndrome 1 | 19 |
| MSH2 | Definitive | Autosomal recessive | mismatch repair cancer syndrome 1 | 17 |
| MSH6 | Definitive | Autosomal recessive | mismatch repair cancer syndrome 1 | 17 |
| PMS2 | Definitive | Autosomal recessive | mismatch repair cancer syndrome 1 | 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
4 cohort genes, 4 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 4 |
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,clinvar |
| PMS2 | HGNC:9122 | ENSG00000122512 | P54278 | Mismatch repair endonuclease PMS2 | gencc,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). |
Protein-family classification
Druggable: 0 · Difficult: 0 · Unknown: 4 · 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 | 4 | 1.8× | 0.097 |
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 |
Expression context
Cohort genes with no expression data: 0.
4 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) | 4 |
| 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 |
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 |
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 |
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: 0 · 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 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 4 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 4 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 | 1053.2× | 2e-11 | MLH1, MSH2, MSH6, PMS2 |
| mismatch repair | 4 | 648.1× | 1e-10 | MLH1, MSH2, MSH6, PMS2 |
| somatic recombination of immunoglobulin gene segments | 3 | 3159.8× | 3e-10 | MSH2, MSH6, PMS2 |
| positive regulation of isotype switching to IgA isotypes | 3 | 2106.5× | 1e-09 | MLH1, MSH2, PMS2 |
| positive regulation of isotype switching to IgG isotypes | 3 | 1149.0× | 7e-09 | MLH1, MSH2, PMS2 |
| isotype switching | 3 | 632.0× | 4e-08 | MLH1, MSH2, MSH6 |
| negative regulation of DNA recombination | 2 | 561.7× | 3e-05 | MSH2, MSH6 |
| determination of adult lifespan | 2 | 216.1× | 2e-04 | MSH2, MSH6 |
| intrinsic apoptotic signaling pathway in response to DNA damage | 2 | 162.0× | 3e-04 | MLH1, MSH6 |
| meiotic mismatch repair | 1 | 4213.0× | 9e-04 | MSH6 |
| somatic recombination of immunoglobulin genes involved in immune response | 1 | 4213.0× | 9e-04 | MSH2 |
| meiotic metaphase I homologous chromosome alignment | 1 | 4213.0× | 9e-04 | MLH1 |
| meiotic spindle midzone assembly | 1 | 2106.5× | 0.002 | MLH1 |
| male meiosis chromosome segregation | 1 | 1404.3× | 0.002 | MLH1 |
| negative regulation of mitotic recombination | 1 | 1404.3× | 0.002 | MLH1 |
| female meiosis chromosome segregation | 1 | 1053.2× | 0.002 | MLH1 |
| B cell mediated immunity | 1 | 1053.2× | 0.002 | MSH2 |
| maintenance of DNA repeat elements | 1 | 842.6× | 0.003 | MSH2 |
| mitotic recombination | 1 | 702.2× | 0.003 | MSH2 |
| DNA repair | 2 | 31.9× | 0.003 | MSH2, MSH6 |
| response to UV-B | 1 | 468.1× | 0.004 | MSH2 |
| meiotic telomere clustering | 1 | 468.1× | 0.004 | MLH1 |
| DNA damage tolerance | 1 | 421.3× | 0.004 | MSH2 |
| oxidative phosphorylation | 1 | 351.1× | 0.005 | MSH2 |
| resolution of meiotic recombination intermediates | 1 | 234.1× | 0.007 | MLH1 |
| mitotic intra-S DNA damage checkpoint signaling | 1 | 234.1× | 0.007 | MSH2 |
| response to X-ray | 1 | 221.7× | 0.007 | MSH2 |
| spermatogenesis | 2 | 17.6× | 0.007 | MLH1, MSH6 |
| nuclear-transcribed mRNA poly(A) tail shortening | 1 | 200.6× | 0.007 | MLH1 |
| homologous chromosome pairing at meiosis | 1 | 150.5× | 0.010 | MLH1 |
Therapeutics
Drug target analysis
Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 3
Druggability breadth: 3 of 4 evidence-associated genes (75%) 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 |
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: 4; with CPIC/DPWG dosing guidelines: 0.
No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).
Drug repurposing candidates
1 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) |
|---|---|---|
| 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 | 3 | MLH1, MSH2, PMS2 |
Undrugged target profiles
3 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 | — |
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 |
|---|---|---|---|
| NCT07461246 | Not specified | ACTIVE_NOT_RECRUITING | Familial Adenomatous Poliposys Italian Network (Rete Italiana Poliposi Adenomatosa Familiare) |