Lynch syndrome 5

Summary

Lynch syndrome 5 (MONDO:0013710) is a disease caused by MSH6 (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: MSH6 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 3,249

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Lynch syndrome 5
Mondo ID	MONDO:0013710
MeSH	C563456
OMIM	614350
DOID	DOID:0070272
UMLS	C1833477
MedGen	318886
GARD	0015792
Is cancer (heuristic)	no

Also known as: colorectal cancer, hereditary nonpolyposis, type 5 · hereditary nonpolyposis colon cancer caused by mutation in MSH6 · HNPCC5 · MSH6 hereditary nonpolyposis colon cancer · MSH6-related Lynch Syndrome

Data availability: 3,249 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 dominant disease › Lynch syndrome › Lynch syndrome 5

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

600 retrieved; paginated sample, class counts are floors:

215 benign/likely benign, 149 pathogenic, 114 conflicting classifications of pathogenicity, 45 pathogenic/likely pathogenic, 35 uncertain significance, 28 likely benign, 14 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1049792	NM_000179.3(MSH6):c.3554_3556+2del	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1050411	NM_000179.3(MSH6):c.2412_2413del (p.Lys804fs)	MSH6	Pathogenic	criteria provided, single submitter
1050732	NM_000179.3(MSH6):c.3083C>A (p.Ser1028Ter)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1068512	NM_000179.3(MSH6):c.2335dup (p.Cys779fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1069248	NM_000179.3(MSH6):c.3424del (p.Thr1142fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1070676	NM_000179.3(MSH6):c.717dup (p.Arg240fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1071630	NM_000179.3(MSH6):c.496del (p.Tyr166fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1071805	NM_000179.3(MSH6):c.1926_1930del (p.Tyr642_Arg644delinsTer)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1072512	NM_000179.3(MSH6):c.2413dup (p.Ile805fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1072643	NM_000179.3(MSH6):c.1392del (p.Ile464fs)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072945	NM_000179.3(MSH6):c.3946_3958dup (p.Ala1320delinsGlyThrTer)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1073540	NM_000179.3(MSH6):c.118del (p.Ala40fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1074383	NM_000179.3(MSH6):c.24C>A (p.Tyr8Ter)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074496	NM_000179.3(MSH6):c.3158_3159del (p.Cys1053fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1075827	NM_000179.3(MSH6):c.642del (p.Thr213_Tyr214insTer)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076190	NM_000179.3(MSH6):c.1939_1948del (p.Leu647fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1076193	NM_000179.3(MSH6):c.2897_2898dup (p.Ile967fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1076375	NM_000179.3(MSH6):c.333C>G (p.Tyr111Ter)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1172057	NM_000179.3(MSH6):c.868del (p.Gly289_Leu290insTer)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1172098	NM_000179.3(MSH6):c.1198G>T (p.Glu400Ter)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1193373	NM_000179.3(MSH6):c.2102dup (p.Leu701fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
127558	NM_000179.3(MSH6):c.1241G>A (p.Trp414Ter)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
127580	NM_000179.3(MSH6):c.3142C>T (p.Gln1048Ter)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
127590	NM_000179.3(MSH6):c.3746_3749dup (p.His1250fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
127598	NM_000179.3(MSH6):c.468_471del (p.Glu158fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
127602	NM_000179.3(MSH6):c.602_603del (p.Glu201fs)	MSH6	Pathogenic	criteria provided, multiple submitters, no conflicts
1301312	NM_000179.3(MSH6):c.2938G>T (p.Glu980Ter)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1301314	NM_000179.3(MSH6):c.2602del (p.Met868fs)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320037	NM_000179.3(MSH6):c.4001+1G>A	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1321397	NM_000179.3(MSH6):c.2872C>T (p.Gln958Ter)	MSH6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 19 · 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
MSH6	Definitive	Autosomal dominant	Lynch syndrome 5	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
RYR1	Orphanet:169186	Autosomal recessive centronuclear myopathy
RYR1	Orphanet:169189	Autosomal dominant centronuclear myopathy
RYR1	Orphanet:178145	Moderate multiminicore disease with hand involvement
RYR1	Orphanet:324581	Benign Samaritan congenital myopathy
RYR1	Orphanet:33108	Lethal multiple pterygium syndrome
RYR1	Orphanet:423	Malignant hyperthermia of anesthesia
RYR1	Orphanet:424107	Congenital myopathy with myasthenic-like onset
RYR1	Orphanet:466650	Exercise-induced malignant hyperthermia
RYR1	Orphanet:597	Central core disease
RYR1	Orphanet:700188	Calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy
RYR1	Orphanet:98905	Congenital multicore myopathy with external ophthalmoplegia
RYR1	Orphanet:99741	King-Denborough syndrome
FBXO11	Orphanet:528084	Non-specific syndromic intellectual disability
MLH1	Orphanet:144	Lynch syndrome
MLH1	Orphanet:252202	Constitutional mismatch repair deficiency syndrome
PMS2	Orphanet:144	Lynch syndrome
PMS2	Orphanet:252202	Constitutional mismatch repair deficiency syndrome

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
MSH6	HGNC:7329	ENSG00000116062	P52701	DNA mismatch repair protein Msh6	gencc,clinvar
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	clinvar
FBXO11	HGNC:13590	ENSG00000138081	Q86XK2	F-box only protein 11	clinvar
MLH1	HGNC:7127	ENSG00000076242	P40692	DNA mismatch repair protein Mlh1	clinvar
PMS2	HGNC:9122	ENSG00000122512	P54278	Mismatch repair endonuclease PMS2	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).
RYR1	Ryanodine receptor 1	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules.
FBXO11	F-box only protein 11	Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins, such as DTL/CDT2, BCL6, SNAI1 and PRDM1/BLI…
MLH1	DNA mismatch repair protein Mlh1	Heterodimerizes with PMS2 to form MutL alpha, a 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: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

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
Ion channel	1	22.3×	0.132
Transcription factor	1	1.6×	0.608
Other/Unknown	3	1.1×	0.608

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
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
FBXO11	Transcription factor	no		F-box_dom, Znf_UBR, PbH1
MLH1	Other/Unknown	no		MutL/Mlh/PMS, DNA_mismatch_S5_2-like, Ribsml_uS5_D2-typ_fold_subgr
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.

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
ganglionic eminence	2
ventricular zone	2
embryo	1
gastrocnemius	1
gluteal muscle	1
hindlimb stylopod muscle	1
cortical plate	1
deltoid	1
skeletal muscle tissue of rectus abdominis	1
tibialis anterior	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
MSH6	293	ubiquitous	marker	ventricular zone, embryo, ganglionic eminence
RYR1	214	broad	marker	gluteal muscle, gastrocnemius, hindlimb stylopod muscle
FBXO11	287	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
MLH1	296	ubiquitous	marker	tibialis anterior, skeletal muscle tissue of rectus abdominis, deltoid
PMS2	143	ubiquitous	marker	thymus, prefrontal cortex, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MLH1	4,435
MSH6	4,091
PMS2	2,658
RYR1	2,177
FBXO11	2,000

Intra-cohort edges

A	B	Sources
FBXO11	MSH6	string_interaction
MLH1	MSH6	string_interaction
MLH1	PMS2	biogrid_interaction, intact, string_interaction
MSH6	PMS2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PMS2	P54278	9
MSH6	P52701	8
MLH1	P40692	7
RYR1	P21817	2
FBXO11	Q86XK2	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 28. Enrichment computed across 5 evidence-associated genes (5 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 5 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	489.4×	4e-07	MSH6, MLH1, PMS2
Defective Mismatch Repair Associated With MLH1	2	2284.0×	1e-06	MLH1, PMS2
Defective Mismatch Repair Associated With PMS2	2	2284.0×	1e-06	MLH1, PMS2
Mismatch Repair	2	1142.0×	5e-06	MSH6, MLH1
Diseases of Mismatch Repair (MMR)	2	1142.0×	5e-06	MSH6, MLH1
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	2	326.3×	6e-05	MLH1, PMS2
Diseases of DNA repair	2	228.4×	1e-04	MSH6, MLH1
TP53 Regulates Transcription of DNA Repair Genes	2	72.5×	0.001	MLH1, PMS2
Defective Mismatch Repair Associated With MSH6	1	1142.0×	0.003	MSH6
DNA Repair	2	39.4×	0.003	MSH6, MLH1
Defective Mismatch Repair Associated With MSH2	1	761.3×	0.003	MSH6
Meiosis	1	57.1×	0.041	MLH1
Ion homeostasis	1	40.8×	0.052	RYR1
Reproduction	1	38.1×	0.052	MLH1
Stimuli-sensing channels	1	27.2×	0.066	RYR1
Meiotic recombination	1	25.9×	0.066	MLH1
Cardiac conduction	1	21.8×	0.074	RYR1
Ion channel transport	1	19.2×	0.075	RYR1
Disease	2	5.2×	0.075	MSH6, MLH1
Muscle contraction	1	15.4×	0.088	RYR1
Transcriptional Regulation by TP53	1	12.4×	0.104	MLH1
Neddylation	1	9.5×	0.129	FBXO11
Antigen processing: Ubiquitination & Proteasome degradation	1	7.4×	0.153	FBXO11
Cell Cycle	1	7.2×	0.153	MLH1
Transport of small molecules	1	5.0×	0.206	RYR1
RNA Polymerase II Transcription	1	4.5×	0.219	MLH1
Gene expression (Transcription)	1	3.6×	0.260	MLH1
Generic Transcription Pathway	1	3.0×	0.290	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 5 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	3	632.0×	3e-07	MSH6, MLH1, PMS2
mismatch repair	3	388.9×	8e-07	MSH6, MLH1, PMS2
somatic recombination of immunoglobulin gene segments	2	1685.2×	7e-06	MSH6, PMS2
positive regulation of isotype switching to IgA isotypes	2	1123.5×	1e-05	MLH1, PMS2
positive regulation of isotype switching to IgG isotypes	2	612.8×	4e-05	MLH1, PMS2
isotype switching	2	337.0×	1e-04	MSH6, MLH1
intrinsic apoptotic signaling pathway in response to DNA damage	2	129.6×	6e-04	MSH6, MLH1
meiotic mismatch repair	1	3370.4×	0.002	MSH6
meiotic metaphase I homologous chromosome alignment	1	3370.4×	0.002	MLH1
meiotic spindle midzone assembly	1	1685.2×	0.003	MLH1
male meiosis chromosome segregation	1	1123.5×	0.004	MLH1
negative regulation of mitotic recombination	1	1123.5×	0.004	MLH1
female meiosis chromosome segregation	1	842.6×	0.004	MLH1
response to caffeine	1	481.5×	0.007	RYR1
meiotic telomere clustering	1	374.5×	0.009	MLH1
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	337.0×	0.009	RYR1
cellular response to caffeine	1	306.4×	0.009	RYR1
ossification involved in bone maturation	1	280.9×	0.009	RYR1
negative regulation of DNA recombination	1	224.7×	0.011	MSH6
resolution of meiotic recombination intermediates	1	187.2×	0.013	MLH1
striated muscle contraction	1	168.5×	0.014	RYR1
nuclear-transcribed mRNA poly(A) tail shortening	1	160.5×	0.014	MLH1
spermatogenesis	2	14.1×	0.016	MSH6, MLH1
homologous chromosome pairing at meiosis	1	120.4×	0.017	MLH1
skeletal muscle fiber development	1	108.7×	0.018	RYR1
skin development	1	88.7×	0.020	RYR1
determination of adult lifespan	1	86.4×	0.020	MSH6
double-strand break repair via nonhomologous end joining	1	84.3×	0.020	MLH1
negative regulation of epithelial to mesenchymal transition	1	82.2×	0.020	FBXO11
oogenesis	1	76.6×	0.020	MLH1

Therapeutics

Drug target analysis

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

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
RYR1	0	0
FBXO11	0	0
MLH1	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
RYR1	16	Binding:13, Functional:3
MSH6	10	Binding:10
FBXO11	2	Binding:2
PMS2	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
RYR1	1

Chemical tractability of cohort targets

1 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

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	1	RYR1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	FBXO11, MLH1, PMS2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FBXO11	2	MSH6
MLH1	0	MSH6
PMS2	1	MSH6
RYR1	16	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.