Mismatch repair cancer syndrome 2

Summary

Mismatch repair cancer syndrome 2 (MONDO:0030840) is a cancer caused by MSH2 (GenCC Definitive), with 1 cohort gene (1 CIViC-evidence somatic driver; 233 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Causal gene: MSH2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 233

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mismatch repair cancer syndrome 2
Mondo ID	MONDO:0030840
OMIM	619096
UMLS	C5436806
MedGen	1750327
GARD	0018362
Is cancer (heuristic)	yes

Also known as: mismatch repair cancer syndrome 2 · MMRCS2 · MSH2-related constitutional mismatch repair deficiency syndrome

Data availability: 233 ClinVar variants · 2 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 2

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

233 retrieved; paginated sample, class counts are floors:

90 conflicting classifications of pathogenicity, 47 pathogenic, 41 uncertain significance, 16 benign/likely benign, 13 likely benign, 11 likely pathogenic, 8 benign, 7 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3779909	NC_000002.12:g.107580437_107580438del		Pathogenic	criteria provided, single submitter
1050772	NM_000251.3(MSH2):c.1387-2del	MSH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066844	NM_000251.3(MSH2):c.641_642insCAAATTGAGTCTAGTGATAA (p.Arg214fs)	MSH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1761296	NM_000251.3(MSH2):c.793-2A>T	MSH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1767061	NM_000251.3(MSH2):c.946del (p.Ser316fs)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1768	NM_000251.3(MSH2):c.454del (p.Met152fs)	MSH2	Pathogenic	reviewed by expert panel
1783959	NM_000251.3(MSH2):c.1072G>T (p.Glu358Ter)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
182584	NM_000251.3(MSH2):c.592G>T (p.Glu198Ter)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1929271	NM_000251.3(MSH2):c.2599G>T (p.Glu867Ter)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
218038	NM_000251.3(MSH2):c.1538_1539del (p.Leu513fs)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
218048	NM_000251.3(MSH2):c.793-1G>A	MSH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
254090	NM_000251.2(MSH2):c.-125_1076+?del	MSH2	Pathogenic	criteria provided, single submitter
36561	NM_000251.3(MSH2):c.1030C>T (p.Gln344Ter)	MSH2	Pathogenic	reviewed by expert panel
36580	NM_000251.3(MSH2):c.942+3A>T	MSH2	Pathogenic	reviewed by expert panel
3779894	NM_000251.3(MSH2):c.1320dup (p.Thr441fs)	MSH2	Pathogenic	criteria provided, single submitter
3779898	NM_000251.3(MSH2):c.1672dup (p.Ser558fs)	MSH2	Pathogenic	criteria provided, single submitter
3779911	NM_000251.3(MSH2):c.212-1_366+711del	MSH2	Pathogenic	criteria provided, single submitter
3779913	NM_000251.3(MSH2):c.924_942del (p.Ala309fs)	MSH2	Pathogenic	criteria provided, single submitter
3779915	NM_000251.3(MSH2):c.1760-1_2006-296del	MSH2	Pathogenic	criteria provided, single submitter
3779916	NM_000251.3(MSH2):c.1760_2005+455del	MSH2	Pathogenic	criteria provided, single submitter
3780869	NM_000251.3(MSH2):c.-1_211+1del	MSH2	Pathogenic	criteria provided, single submitter
3780870	NM_000251.3(MSH2):c.-1_211+156del	MSH2	Pathogenic	criteria provided, single submitter
3780871	NM_000251.3(MSH2):c.-1_211+866del	MSH2	Pathogenic	criteria provided, single submitter
3780872	NM_000251.3(MSH2):c.-1_211+1176del	MSH2	Pathogenic	criteria provided, single submitter
3780873	NM_000251.3(MSH2):c.1_211del (p.Met1fs)	MSH2	Pathogenic	criteria provided, single submitter
3780874	NM_000251.3(MSH2):c.213_1076+1del	MSH2	Pathogenic	criteria provided, single submitter
3891723	NC_000002.11:g.47630331_47643568dup	MSH2	Pathogenic	criteria provided, single submitter
428475	NM_000251.3(MSH2):c.680_683del (p.Arg227fs)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
428507	NM_000251.3(MSH2):c.940C>T (p.Gln314Ter)	MSH2	Pathogenic	criteria provided, multiple submitters, no conflicts
483664	NM_000251.3(MSH2):c.1661G>A (p.Ser554Asn)	MSH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

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
MSH2			CIViC #3628

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
MSH2	Definitive	Autosomal recessive	mismatch repair cancer syndrome 1	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MSH2	Orphanet:144	Lynch syndrome
MSH2	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
MSH2	HGNC:7325	ENSG00000095002	P43246	DNA mismatch repair protein Msh2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MSH2	DNA mismatch repair protein Msh2	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)
MSH2	Other/Unknown	no		DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS-lik_N, DNA_mismatch_repair_MutS_core

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
oocyte	1
secondary oocyte	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MSH2	278	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MSH2	4,537

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MSH2	P43246	30

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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 MSH3	1	5710.0×	0.001	MSH2
Defective Mismatch Repair Associated With MSH6	1	5710.0×	0.001	MSH2
Defective Mismatch Repair Associated With MSH2	1	3806.7×	0.001	MSH2
Mismatch Repair	1	2855.0×	0.001	MSH2
Diseases of Mismatch Repair (MMR)	1	2855.0×	0.001	MSH2
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	1	815.7×	0.003	MSH2
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	1	815.7×	0.003	MSH2
Diseases of DNA repair	1	571.0×	0.003	MSH2
TP53 Regulates Transcription of DNA Repair Genes	1	181.3×	0.009	MSH2
DNA Repair	1	98.5×	0.015	MSH2
Transcriptional Regulation by TP53	1	62.1×	0.022	MSH2
RNA Polymerase II Transcription	1	22.5×	0.055	MSH2
Gene expression (Transcription)	1	17.8×	0.065	MSH2
Generic Transcription Pathway	1	15.1×	0.071	MSH2
Disease	1	13.1×	0.076	MSH2

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
somatic recombination of immunoglobulin genes involved in immune response	1	16852.0×	0.001	MSH2
somatic recombination of immunoglobulin gene segments	1	4213.0×	0.001	MSH2
B cell mediated immunity	1	4213.0×	0.001	MSH2
maintenance of DNA repeat elements	1	3370.4×	0.001	MSH2
mitotic recombination	1	2808.7×	0.001	MSH2
positive regulation of isotype switching to IgA isotypes	1	2808.7×	0.001	MSH2
response to UV-B	1	1872.4×	0.002	MSH2
DNA damage tolerance	1	1685.2×	0.002	MSH2
positive regulation of isotype switching to IgG isotypes	1	1532.0×	0.002	MSH2
oxidative phosphorylation	1	1404.3×	0.002	MSH2
negative regulation of DNA recombination	1	1123.5×	0.002	MSH2
somatic hypermutation of immunoglobulin genes	1	1053.2×	0.002	MSH2
mitotic intra-S DNA damage checkpoint signaling	1	936.2×	0.002	MSH2
response to X-ray	1	887.0×	0.002	MSH2
isotype switching	1	842.6×	0.002	MSH2
mismatch repair	1	648.1×	0.002	MSH2
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	1	495.6×	0.003	MSH2
germ cell development	1	455.5×	0.003	MSH2
determination of adult lifespan	1	432.1×	0.003	MSH2
B cell differentiation	1	218.9×	0.006	MSH2
double-strand break repair	1	203.0×	0.006	MSH2
male gonad development	1	156.0×	0.007	MSH2
negative regulation of neuron apoptotic process	1	110.9×	0.010	MSH2
in utero embryonic development	1	72.0×	0.014	MSH2
DNA repair	1	63.8×	0.016	MSH2

Therapeutics

Drug target analysis

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

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
MSH2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MSH2	9	Binding:9

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

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MSH2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MSH2	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.