Mismatch repair cancer syndrome 4

Summary

Mismatch repair cancer syndrome 4 (MONDO:0030843) is a cancer caused by PMS2 (GenCC Definitive), with 1 cohort gene (1 CIViC-evidence somatic driver; 230 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Causal gene: PMS2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 230

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mismatch repair cancer syndrome 4
Mondo ID	MONDO:0030843
OMIM	619101
UMLS	C5436817
MedGen	1745382
GARD	0018364
Is cancer (heuristic)	yes

Also known as: mismatch repair cancer syndrome 4 · MMRCS4 · PMS2-related constitutional mismatch repair deficiency syndrome

Data availability: 230 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 4

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

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

230 retrieved; paginated sample, class counts are floors:

82 conflicting classifications of pathogenicity, 52 uncertain significance, 43 pathogenic, 23 pathogenic/likely pathogenic, 17 benign/likely benign, 4 benign, 4 likely benign, 4 likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
3780919	NM_000535.7(PMS2):c.1_705del705 (p.Met1_Gln235del)	LOC129997916	Pathogenic	criteria provided, single submitter
127789	NM_000535.7(PMS2):c.319C>T (p.Arg107Trp)	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127796	NM_000535.7(PMS2):c.823C>T (p.Gln275Ter)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
135067	NM_000535.7(PMS2):c.1687C>T (p.Arg563Ter)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
140880	NM_000535.7(PMS2):c.904-2A>G	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
140957	NM_000535.7(PMS2):c.1067del (p.Lys356fs)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
141280	NM_000535.7(PMS2):c.2500_2501delinsG (p.Met834fs)	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
141395	NM_000535.7(PMS2):c.325del (p.Glu109fs)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
141871	NM_000535.7(PMS2):c.23+1G>T	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162508	NM_000535.7(PMS2):c.1144+1G>A	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1768663	NM_000535.7(PMS2):c.993C>A (p.Cys331Ter)	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183716	NM_000535.7(PMS2):c.765C>A (p.Tyr255Ter)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
183732	NM_000535.7(PMS2):c.809C>G (p.Ser270Ter)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
192316	NM_000535.7(PMS2):c.2002A>G (p.Ile668Val)	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1929394	NM_000535.7(PMS2):c.989-1G>A	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215994	NM_000535.7(PMS2):c.537+1G>A	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
216072	NM_000535.7(PMS2):c.1239dup (p.Asp414fs)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
234508	NM_000535.7(PMS2):c.631C>T (p.Arg211Ter)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
234604	NM_000535.7(PMS2):c.2445+1G>T	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
234673	NM_000535.7(PMS2):c.1778del (p.Lys593fs)	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2451601	NM_000535.7(PMS2):c.778_781del (p.Ser260fs)	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2573186	NM_000535.7(PMS2):c.1903G>T (p.Glu635Ter)	PMS2	Pathogenic	criteria provided, single submitter
2674268	NM_000535.7(PMS2):c.1934dup (p.Tyr645Ter)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
3379238	NM_000535.7(PMS2):c.1882_1886dup (p.Lys630fs)	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3594737	NM_000535.7(PMS2):c.745_746insCTGCCCACAC (p.Asp249fs)	PMS2	Pathogenic	criteria provided, single submitter
3780455	NM_000535.7(PMS2):c.806dup (p.Ser270fs)	PMS2	Pathogenic	criteria provided, single submitter
3780908	NC_000007.13:g.(?6036957)(6037054_?)del	PMS2	Pathogenic	criteria provided, single submitter
3780911	NM_000535.7(PMS2):c.2007_2589del583 (p.Lys670fs)	PMS2	Pathogenic	criteria provided, single submitter
3780916	NM_000535.7(PMS2):c.1145-1_2006+1del	PMS2	Pathogenic	criteria provided, single submitter
3892132	NM_000535.7(PMS2):c.2357_2445+509del	PMS2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
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
PMS2	Definitive	Autosomal recessive	mismatch repair cancer syndrome 1	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PMS2	Orphanet:144	Lynch syndrome
PMS2	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
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)
PMS2	Mismatch repair endonuclease PMS2	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)
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.

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
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
PMS2	143	ubiquitous	marker	thymus, prefrontal cortex, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PMS2	2,658

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PMS2	P54278	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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 MLH1	1	5710.0×	4e-04	PMS2
Defective Mismatch Repair Associated With PMS2	1	5710.0×	4e-04	PMS2
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	1	815.7×	0.002	PMS2
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	1	815.7×	0.002	PMS2
TP53 Regulates Transcription of DNA Repair Genes	1	181.3×	0.006	PMS2

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 gene segments	1	4213.0×	0.001	PMS2
positive regulation of isotype switching to IgA isotypes	1	2808.7×	0.001	PMS2
positive regulation of isotype switching to IgG isotypes	1	1532.0×	0.001	PMS2
somatic hypermutation of immunoglobulin genes	1	1053.2×	0.001	PMS2
mismatch repair	1	648.1×	0.002	PMS2
response to xenobiotic stimulus	1	69.1×	0.014	PMS2

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
PMS2	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
PMS2	1	Binding:1

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	PMS2

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)
PMS2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.