Mismatch repair cancer syndrome 3

Summary

Mismatch repair cancer syndrome 3 (MONDO:0030841) is a cancer caused by MSH6 (GenCC Definitive), with 1 cohort gene (1 CIViC-evidence somatic driver; 324 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Causal gene: MSH6 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 324

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mismatch repair cancer syndrome 3
Mondo ID	MONDO:0030841
OMIM	619097
UMLS	C5436807
MedGen	1733656
GARD	0018363
Is cancer (heuristic)	yes

Also known as: mismatch repair cancer syndrome 3 · MMRCS3 · MSH6-related constitutional mismatch repair deficiency syndrome

Data availability: 324 ClinVar variants · 3 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 recessive disease › mismatch repair cancer syndrome › mismatch repair cancer syndrome 3

Related subtypes (3): mismatch repair cancer syndrome 1, mismatch repair cancer syndrome 2, mismatch repair cancer syndrome 4

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

324 retrieved; paginated sample, class counts are floors:

137 conflicting classifications of pathogenicity, 66 uncertain significance, 49 pathogenic, 34 benign/likely benign, 16 pathogenic/likely pathogenic, 10 likely benign, 6 likely pathogenic, 6 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069617	NM_000179.3(MSH6):c.467C>A (p.Ser156Ter)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1319971	NM_000179.3(MSH6):c.1453C>T (p.Gln485Ter)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
140866	NM_000179.3(MSH6):c.3725G>A (p.Arg1242His)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
142620	NM_000179.3(MSH6):c.2653A>T (p.Lys885Ter)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
142773	NM_000179.3(MSH6):c.3469G>T (p.Gly1157Cys)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
142781	NM_000179.3(MSH6):c.3037_3041del (p.Lys1013fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1727781	NM_000179.3(MSH6):c.3114_3115dup (p.Asn1039fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1733516	NM_000179.3(MSH6):c.3640G>T (p.Glu1214Ter)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1780582	NM_000179.3(MSH6):c.1810G>T (p.Glu604Ter)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1794255	NM_000179.3(MSH6):c.2646del (p.Phe882fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1796639	NM_000179.3(MSH6):c.2836_2837del (p.Glu946fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
183723	NM_000179.3(MSH6):c.10C>T (p.Gln4Ter)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183794	NM_000179.3(MSH6):c.3743_3744insT (p.Tyr1249fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
184998	NM_000179.3(MSH6):c.3980_3983dup (p.Leu1330fs)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
186304	NM_000179.3(MSH6):c.989C>A (p.Ser330Ter)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
187691	NM_000179.3(MSH6):c.2906_2907del (p.Tyr969fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
218062	NM_000179.3(MSH6):c.3528_3532del (p.Leu1177fs)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218069	NM_000179.3(MSH6):c.3699_3702dup (p.Leu1235fs)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
233242	NM_000179.3(MSH6):c.3417C>T (p.Gly1139=)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
233651	NM_000179.3(MSH6):c.1134_1135del (p.Arg379_Asp380insTer)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
234794	NM_000179.3(MSH6):c.3753_3756dup (p.Val1253fs)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
237133	NM_000179.3(MSH6):c.1350_1351del (p.Phe451fs)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2453171	NM_000179.3(MSH6):c.3277G>T (p.Gly1093Ter)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
2673600	NM_000179.3(MSH6):c.3577G>T (p.Glu1193Ter)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3381941	NM_000179.3(MSH6):c.3886_3887insT (p.Lys1296fs)	MSH6	Pathogenic	criteria provided, single submitter
3398930	NM_000179.3(MSH6):c.2139_2140del (p.Asp713_Ser714insTer)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36593	NM_000179.3(MSH6):c.3699_3702del (p.Lys1233fs)	MSH6	Pathogenic	reviewed by expert panel
372414	NM_000179.3(MSH6):c.3573dup (p.Val1192fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
3779948	NM_000179.3(MSH6):c.3637dup (p.Asp1213fs)	MSH6	Pathogenic	criteria provided, single submitter
3779954	NM_000179.3(MSH6):c.2277_2293del (p.Glu760fs)	MSH6	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
MSH6			CIViC #2478

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
MSH6	Definitive	Autosomal recessive	mismatch repair cancer syndrome 1	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MSH6	Orphanet:144	Lynch syndrome
MSH6	Orphanet:252202	Constitutional mismatch repair deficiency syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MSH6	HGNC:7329	ENSG00000116062	P52701	DNA mismatch repair protein Msh6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MSH6	DNA mismatch repair protein Msh6	Component of the post-replicative DNA mismatch repair system (MMR).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MSH6	Other/Unknown	no		PWWP_dom, DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS-lik_N

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
embryo	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MSH6	293	ubiquitous	marker	ventricular zone, embryo, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MSH6	4,091

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MSH6	P52701	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective Mismatch Repair Associated With MSH6	1	5710.0×	7e-04	MSH6
Defective Mismatch Repair Associated With MSH2	1	3806.7×	7e-04	MSH6
Mismatch Repair	1	2855.0×	7e-04	MSH6
Diseases of Mismatch Repair (MMR)	1	2855.0×	7e-04	MSH6
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	1	815.7×	0.002	MSH6
Diseases of DNA repair	1	571.0×	0.002	MSH6
DNA Repair	1	98.5×	0.012	MSH6
Disease	1	13.1×	0.076	MSH6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
meiotic mismatch repair	1	16852.0×	7e-04	MSH6
somatic recombination of immunoglobulin gene segments	1	4213.0×	0.001	MSH6
negative regulation of DNA recombination	1	1123.5×	0.003	MSH6
somatic hypermutation of immunoglobulin genes	1	1053.2×	0.003	MSH6
isotype switching	1	842.6×	0.003	MSH6
mismatch repair	1	648.1×	0.003	MSH6
determination of adult lifespan	1	432.1×	0.004	MSH6
response to UV	1	366.4×	0.004	MSH6
intrinsic apoptotic signaling pathway	1	358.6×	0.004	MSH6
intrinsic apoptotic signaling pathway in response to DNA damage	1	324.1×	0.004	MSH6
DNA repair	1	63.8×	0.017	MSH6
spermatogenesis	1	35.2×	0.028	MSH6

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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

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

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.