Lynch syndrome 4

Summary

Lynch syndrome 4 (MONDO:0013699) is a disease caused by PMS2 (GenCC Definitive), with 5 cohort genes. The dominant Reactome pathway is Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) (3 cohort genes).

At a glance

• Causal gene: PMS2 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 2,003

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Lynch syndrome 4
Mondo ID	MONDO:0013699
MeSH	C563971
OMIM	614337
DOID	DOID:0070275
UMLS	C1838333
MedGen	325005
GARD	0015791
Is cancer (heuristic)	no

Also known as: colorectal cancer, hereditary nonpolyposis, type 4 · hereditary nonpolyposis colon cancer caused by mutation in PMS2 · HNPCC4 · PMS2 hereditary nonpolyposis colon cancer · PMS2-related Lynch syndrome

Data availability: 2,003 ClinVar variants · 6 ClinGen variant curations · 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 dominant disease › Lynch syndrome › Lynch syndrome 4

Related subtypes (4): Lynch syndrome 1, Lynch syndrome 2, Lynch syndrome 8, Lynch syndrome 5

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:

207 benign/likely benign, 146 conflicting classifications of pathogenicity, 84 uncertain significance, 60 pathogenic, 49 pathogenic/likely pathogenic, 41 likely benign, 11 likely pathogenic, 1 not provided, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1049418	NM_000535.7(PMS2):c.368del (p.Ser123fs)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1049809	NM_000535.7(PMS2):c.2506del (p.Glu836fs)	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1049894	NM_000535.7(PMS2):c.1144+1del	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068755	NM_000535.7(PMS2):c.2179C>T (p.Gln727Ter)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1068926	NM_000535.7(PMS2):c.2208del (p.Ala737fs)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1069911	NM_000535.7(PMS2):c.42del (p.Ile15fs)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1073933	NM_000535.7(PMS2):c.2174+1G>C	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074077	NM_000535.7(PMS2):c.735dup (p.Pro246fs)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1074176	NM_000535.7(PMS2):c.1557T>G (p.Tyr519Ter)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1074859	NM_000535.7(PMS2):c.1009dup (p.Thr337fs)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1171824	NM_000535.7(PMS2):c.1239del (p.Asp414fs)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1177380	NM_000535.7(PMS2):c.525del (p.Asn176fs)	PMS2	Pathogenic	criteria provided, single submitter
1192211	NM_000535.7(PMS2):c.2444_2445insTT (p.Val816fs)	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127788	NM_000535.7(PMS2):c.2T>C (p.Met1Thr)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
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
127802	NM_000535.7(PMS2):c.989-1G>T	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1330001	NM_000535.7(PMS2):c.1938del (p.Lys647fs)	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332637	NM_000535.7(PMS2):c.163+1G>T	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1350177	NM_000535.7(PMS2):c.325G>T (p.Glu109Ter)	PMS2	Pathogenic/Likely 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
1352889	NM_000535.7(PMS2):c.1605_1606del (p.Gln536fs)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1393658	NM_000535.7(PMS2):c.2469_2473del (p.Asn823fs)	PMS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1393669	NM_000535.7(PMS2):c.2397_2400dup (p.Ser801fs)	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1404626	NM_000535.7(PMS2):c.1924del (p.Glu642fs)	PMS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
140847	NM_000535.7(PMS2):c.2095G>C (p.Asp699His)	PMS2	Pathogenic/Likely 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
1411804	NM_000535.7(PMS2):c.869del (p.Phe290fs)	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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 12 · 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
PMS2	Definitive	Autosomal dominant	Lynch syndrome	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
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
PMS1	Orphanet:144	Lynch syndrome
RB1	Orphanet:1587	Monosomy 13q14 syndrome
RB1	Orphanet:357027	Hereditary retinoblastoma
RB1	Orphanet:357034	Non-hereditary retinoblastoma
RB1	Orphanet:668	Osteosarcoma
RB1	Orphanet:70573	Small cell lung cancer

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
PMS2	HGNC:9122	ENSG00000122512	P54278	Mismatch repair endonuclease PMS2	gencc,clinvar
MSH2	HGNC:7325	ENSG00000095002	P43246	DNA mismatch repair protein Msh2	clinvar
MSH6	HGNC:7329	ENSG00000116062	P52701	DNA mismatch repair protein Msh6	clinvar
PMS1	HGNC:9121	ENSG00000064933	P54277	PMS1 protein homolog 1	clinvar
RB1	HGNC:9884	ENSG00000139687	P06400	Retinoblastoma-associated protein	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).
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).
PMS1	PMS1 protein homolog 1	Probably involved in the repair of mismatches in DNA.
RB1	Retinoblastoma-associated protein	Tumor suppressor that is a key regulator of the G1/S transition of the cell cycle.

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)
PMS2	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
PMS1	Other/Unknown	no		MutL/Mlh/PMS, HMG_box_dom, DNA_mismatch_S5_2-like
RB1	Other/Unknown	no		RB_B, RB_A, Cyclin-like_dom

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
male germ line stem cell (sensu Vertebrata) in testis	1
prefrontal cortex	1
thymus	1
oocyte	1
secondary oocyte	1
embryo	1
ganglionic eminence	1
left testis	1
male germ cell	1
sperm	1
choroid plexus epithelium	1
epithelium of nasopharynx	1
visceral pleura	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
MSH2	278	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone
MSH6	293	ubiquitous	marker	ventricular zone, embryo, ganglionic eminence
PMS1	286	ubiquitous	marker	sperm, male germ cell, left testis
RB1	287	ubiquitous	marker	epithelium of nasopharynx, choroid plexus epithelium, visceral pleura

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MSH2	4,537
RB1	4,374
MSH6	4,091
PMS2	2,658
PMS1	2,238

Intra-cohort edges

A	B	Sources
MSH2	MSH6	biogrid_interaction, intact, string_interaction
MSH2	PMS1	string_interaction
MSH2	PMS2	string_interaction
MSH6	PMS1	string_interaction
MSH6	PMS2	string_interaction
PMS1	PMS2	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MSH2	P43246	30
RB1	P06400	19
PMS2	P54278	9
MSH6	P52701	8
PMS1	P54277	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 35. 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)	3	611.8×	2e-07	PMS2, MSH2, MSH6
Defective Mismatch Repair Associated With MSH6	2	2855.0×	2e-06	MSH2, MSH6
Defective Mismatch Repair Associated With MSH2	2	1903.3×	3e-06	MSH2, MSH6
Mismatch Repair	2	1427.5×	4e-06	MSH2, MSH6
Diseases of Mismatch Repair (MMR)	2	1427.5×	4e-06	MSH2, MSH6
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	2	407.9×	5e-05	PMS2, MSH2
Diseases of DNA repair	2	285.5×	9e-05	MSH2, MSH6
TP53 Regulates Transcription of DNA Repair Genes	2	90.6×	8e-04	PMS2, MSH2
Defective translocation of RB1 mutants to the nucleus	1	2855.0×	0.001	RB1
Defective Mismatch Repair Associated With MLH1	1	1427.5×	0.002	PMS2
Defective Mismatch Repair Associated With MSH3	1	1427.5×	0.002	MSH2
Defective Mismatch Repair Associated With PMS2	1	1427.5×	0.002	PMS2
DNA Repair	2	49.2×	0.002	MSH2, MSH6
Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes	1	713.8×	0.003	RB1
Replication of the SARS-CoV-1 genome	1	713.8×	0.003	RB1
Replication of the SARS-CoV-2 genome	1	713.8×	0.003	RB1
Positive Regulation of CDH1 Gene Transcription	1	237.9×	0.009	RB1
Inhibition of replication initiation of damaged DNA by RB1/E2F1	1	203.9×	0.010	RB1
Formation of Senescence-Associated Heterochromatin Foci (SAHF)	1	167.9×	0.011	RB1
Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)	1	158.6×	0.011	RB1
Aberrant regulation of mitotic exit in cancer due to RB1 defects	1	129.8×	0.013	RB1
RUNX2 regulates osteoblast differentiation	1	114.2×	0.014	RB1
Oncogene Induced Senescence	1	84.0×	0.018	RB1
Nuclear events stimulated by ALK signaling in cancer	1	81.6×	0.018	RB1
Cyclin E associated events during G1/S transition	1	71.4×	0.020	RB1
Cyclin A:Cdk2-associated events at S phase entry	1	66.4×	0.020	RB1
Cyclin D associated events in G1	1	58.3×	0.022	RB1
APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1	1	42.6×	0.029	RB1
Condensation of Prophase Chromosomes	1	39.1×	0.031	RB1
Disease	2	6.5×	0.037	MSH2, 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mismatch repair	4	518.5×	2e-09	PMS2, MSH2, MSH6, PMS1
somatic recombination of immunoglobulin gene segments	3	2527.8×	2e-09	PMS2, MSH2, MSH6
somatic hypermutation of immunoglobulin genes	3	632.0×	2e-07	PMS2, MSH2, MSH6
positive regulation of isotype switching to IgA isotypes	2	1123.5×	2e-05	PMS2, MSH2
positive regulation of isotype switching to IgG isotypes	2	612.8×	7e-05	PMS2, MSH2
negative regulation of DNA recombination	2	449.4×	1e-04	MSH2, MSH6
isotype switching	2	337.0×	2e-04	MSH2, MSH6
determination of adult lifespan	2	172.8×	6e-04	MSH2, MSH6
meiotic mismatch repair	1	3370.4×	0.003	MSH6
somatic recombination of immunoglobulin genes involved in immune response	1	3370.4×	0.003	MSH2
sister chromatid biorientation	1	1123.5×	0.006	RB1
glial cell apoptotic process	1	1123.5×	0.006	RB1
B cell mediated immunity	1	842.6×	0.006	MSH2
maintenance of mitotic sister chromatid cohesion	1	842.6×	0.006	RB1
regulation of lipid kinase activity	1	842.6×	0.006	RB1
positive regulation of extracellular matrix organization	1	842.6×	0.006	RB1
positive regulation of collagen fibril organization	1	842.6×	0.006	RB1
negative regulation of myofibroblast differentiation	1	842.6×	0.006	RB1
maintenance of DNA repeat elements	1	674.1×	0.007	MSH2
mitotic recombination	1	561.7×	0.007	MSH2
negative regulation of hepatocyte apoptotic process	1	561.7×	0.007	RB1
enucleate erythrocyte differentiation	1	421.3×	0.008	RB1
protein localization to chromosome, centromeric region	1	421.3×	0.008	RB1
positive regulation of transcription regulatory region DNA binding	1	421.3×	0.008	RB1
response to xenobiotic stimulus	2	27.6×	0.008	PMS2, PMS1
DNA repair	2	25.5×	0.008	MSH2, MSH6
response to UV-B	1	374.5×	0.008	MSH2
DNA damage tolerance	1	337.0×	0.009	MSH2
negative regulation of glial cell proliferation	1	337.0×	0.009	RB1
cell morphogenesis involved in neuron differentiation	1	306.4×	0.009	RB1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 2 · Undrugged: 3

Druggability breadth: 4 of 5 evidence-associated genes (80%) 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
RB1	1	2
PMS2	0	0
MSH2	0	0
PMS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	MSH6
EBVACICLIB	2	RB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RB1	59	Binding:59
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

2 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
EBVACICLIB	2	RB1

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	2	MSH6, RB1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	PMS2, MSH2, PMS1

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)
PMS2	1	MSH6
PMS1	0	MSH6
MSH2	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.