Lynch syndrome 2

Summary

Lynch syndrome 2 (MONDO:0012249) is a disease caused by MLH1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: MLH1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 2,177

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Lynch syndrome 2
Mondo ID	MONDO:0012249
MeSH	D055847
OMIM	609310
DOID	DOID:0070274
NCIT	C6726
UMLS	C1333991
MedGen	232603
GARD	0015457
Is cancer (heuristic)	no

Also known as: COCA2 · colorectal cancer, hereditary nonpolyposis, type 2 · familial non-polyposis colon cancer type 2 · Hereditary non-polyposis colon cancer type 2 · Hereditary nonpolyposis colorectal cancer type 2 · HNPCC2 · Lynch 2 syndrome · MLH1-related Lynch syndrome

Data availability: 2,177 ClinVar variants · 2 ClinGen variant curations · 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 dominant disease › Lynch syndrome › Lynch syndrome 2

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

167 benign/likely benign, 152 conflicting classifications of pathogenicity, 138 pathogenic, 45 likely benign, 40 uncertain significance, 37 pathogenic/likely pathogenic, 16 likely pathogenic, 5 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1048862	NM_000249.4(MLH1):c.497T>G (p.Leu166Ter)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1049302	NM_000249.4(MLH1):c.1275dup (p.Gln426fs)	MLH1	Pathogenic	criteria provided, single submitter
1049670	NM_000249.4(MLH1):c.1896+1G>C	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1049673	NM_000249.4(MLH1):c.1367del (p.Thr455_Ser456insTer)	MLH1	Pathogenic	criteria provided, single submitter
1068033	NM_000249.4(MLH1):c.1038+1G>A	MLH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068563	NM_000249.4(MLH1):c.1921dup (p.Leu641fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1068948	NM_000249.4(MLH1):c.406A>T (p.Lys136Ter)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070239	NM_000249.4(MLH1):c.22del (p.Ile8fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070756	NM_000249.4(MLH1):c.1408A>T (p.Arg470Ter)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073257	NM_000249.4(MLH1):c.1707del (p.Asn570fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1074205	NM_000249.4(MLH1):c.35del (p.Asp12fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1074878	NM_000249.4(MLH1):c.1830C>G (p.Tyr610Ter)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1076485	NM_000249.4(MLH1):c.1435_1453del (p.Val479fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1076792	NM_000249.4(MLH1):c.1983dup (p.Thr662fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1177381	NM_000249.4(MLH1):c.1695_1698del (p.Ile565fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1195084	NM_000249.4(MLH1):c.1713del (p.Phe571fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
127610	NM_000249.4(MLH1):c.117-1G>A	MLH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1319487	NM_000249.4(MLH1):c.453+1G>A	MLH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1329486	NM_000249.4(MLH1):c.157G>T (p.Glu53Ter)	MLH1	Pathogenic	criteria provided, single submitter
1332889	NM_000249.4(MLH1):c.1731+2247_1897-402del	MLH1	Pathogenic	no assertion criteria provided
135851	NM_000249.4(MLH1):c.2190del (p.Pro731fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1365840	NM_000249.4(MLH1):c.52_59del (p.Arg18fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1368790	NM_000249.4(MLH1):c.592G>T (p.Gly198Ter)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1392794	NM_000249.4(MLH1):c.1499del (p.Ile500fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1402505	NM_000249.4(MLH1):c.1809del (p.Glu605fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
1404368	NM_000249.4(MLH1):c.816del (p.Arg273fs)	MLH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1405246	NM_000249.4(MLH1):c.1239dup (p.Glu414fs)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
141043	NM_000249.4(MLH1):c.790+1G>T	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts
141177	NM_000249.4(MLH1):c.971dup (p.Arg325fs)	MLH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1412554	NM_000249.4(MLH1):c.1730C>A (p.Ser577Ter)	MLH1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 4 · 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
MLH1	Definitive	Autosomal dominant	Lynch syndrome 2	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MLH1	Orphanet:144	Lynch syndrome
MLH1	Orphanet:252202	Constitutional mismatch repair deficiency syndrome
MSH2	Orphanet:144	Lynch syndrome
MSH2	Orphanet:252202	Constitutional mismatch repair deficiency syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MLH1	HGNC:7127	ENSG00000076242	P40692	DNA mismatch repair protein Mlh1	gencc,clinvar
LRRFIP2	HGNC:6703	ENSG00000093167	Q9Y608	Leucine-rich repeat flightless-interacting protein 2	clinvar
MSH2	HGNC:7325	ENSG00000095002	P43246	DNA mismatch repair protein Msh2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MLH1	DNA mismatch repair protein Mlh1	Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR).
LRRFIP2	Leucine-rich repeat flightless-interacting protein 2	May function as activator of the canonical Wnt signaling pathway, in association with DVL3, upstream of CTNNB1/beta-catenin.
MSH2	DNA mismatch repair protein Msh2	Component of the post-replicative DNA mismatch repair system (MMR).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MLH1	Other/Unknown	no		MutL/Mlh/PMS, DNA_mismatch_S5_2-like, Ribsml_uS5_D2-typ_fold_subgr
LRRFIP2	Other/Unknown	no		LRRFIP1/2
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.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
deltoid	1
skeletal muscle tissue of rectus abdominis	1
tibialis anterior	1
buccal mucosa cell	1
calcaneal tendon	1
tendon	1
oocyte	1
secondary oocyte	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MLH1	296	ubiquitous	marker	tibialis anterior, skeletal muscle tissue of rectus abdominis, deltoid
LRRFIP2	286	ubiquitous	marker	buccal mucosa cell, calcaneal tendon, tendon
MSH2	278	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MSH2	4,537
MLH1	4,435
LRRFIP2	941

Intra-cohort edges

A	B	Sources
MLH1	MSH2	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MSH2	P43246	30
MLH1	P40692	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LRRFIP2	Q9Y608	68.23

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mismatch Repair	2	2855.0×	1e-06	MLH1, MSH2
Diseases of Mismatch Repair (MMR)	2	2855.0×	1e-06	MLH1, MSH2
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	2	815.7×	7e-06	MLH1, MSH2
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	2	815.7×	7e-06	MLH1, MSH2
Diseases of DNA repair	2	571.0×	1e-05	MLH1, MSH2
TP53 Regulates Transcription of DNA Repair Genes	2	181.3×	1e-04	MLH1, MSH2
DNA Repair	2	98.5×	3e-04	MLH1, MSH2
Defective Mismatch Repair Associated With MLH1	1	2855.0×	6e-04	MLH1
Defective Mismatch Repair Associated With MSH3	1	2855.0×	6e-04	MSH2
Defective Mismatch Repair Associated With MSH6	1	2855.0×	6e-04	MSH2
Defective Mismatch Repair Associated With PMS2	1	2855.0×	6e-04	MLH1
Transcriptional Regulation by TP53	2	62.1×	6e-04	MLH1, MSH2
Defective Mismatch Repair Associated With MSH2	1	1903.3×	8e-04	MSH2
RNA Polymerase II Transcription	2	22.5×	0.003	MLH1, MSH2
Gene expression (Transcription)	2	17.8×	0.004	MLH1, MSH2
Generic Transcription Pathway	2	15.1×	0.006	MLH1, MSH2
Disease	2	13.1×	0.007	MLH1, MSH2
Meiosis	1	142.8×	0.008	MLH1
Reproduction	1	95.2×	0.012	MLH1
Meiotic recombination	1	64.9×	0.016	MLH1
Cell Cycle	1	18.0×	0.055	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of isotype switching to IgA isotypes	2	1872.4×	1e-05	MLH1, MSH2
positive regulation of isotype switching to IgG isotypes	2	1021.3×	2e-05	MLH1, MSH2
somatic hypermutation of immunoglobulin genes	2	702.2×	3e-05	MLH1, MSH2
isotype switching	2	561.7×	4e-05	MLH1, MSH2
mismatch repair	2	432.1×	6e-05	MLH1, MSH2
somatic recombination of immunoglobulin genes involved in immune response	1	5617.3×	0.001	MSH2
meiotic metaphase I homologous chromosome alignment	1	5617.3×	0.001	MLH1
meiotic spindle midzone assembly	1	2808.7×	0.002	MLH1
male meiosis chromosome segregation	1	1872.4×	0.002	MLH1
negative regulation of mitotic recombination	1	1872.4×	0.002	MLH1
female meiosis chromosome segregation	1	1404.3×	0.002	MLH1
somatic recombination of immunoglobulin gene segments	1	1404.3×	0.002	MSH2
B cell mediated immunity	1	1404.3×	0.002	MSH2
maintenance of DNA repeat elements	1	1123.5×	0.003	MSH2
mitotic recombination	1	936.2×	0.003	MSH2
response to UV-B	1	624.1×	0.004	MSH2
meiotic telomere clustering	1	624.1×	0.004	MLH1
DNA damage tolerance	1	561.7×	0.004	MSH2
oxidative phosphorylation	1	468.1×	0.005	MSH2
negative regulation of DNA recombination	1	374.5×	0.005	MSH2
resolution of meiotic recombination intermediates	1	312.1×	0.006	MLH1
mitotic intra-S DNA damage checkpoint signaling	1	312.1×	0.006	MSH2
response to X-ray	1	295.6×	0.006	MSH2
nuclear-transcribed mRNA poly(A) tail shortening	1	267.5×	0.006	MLH1
homologous chromosome pairing at meiosis	1	200.6×	0.008	MLH1
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	1	165.2×	0.010	MSH2
germ cell development	1	151.8×	0.010	MSH2
determination of adult lifespan	1	144.0×	0.010	MSH2
double-strand break repair via nonhomologous end joining	1	140.4×	0.010	MLH1
oogenesis	1	127.7×	0.011	MLH1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MLH1	0	0
LRRFIP2	0	0
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: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 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.

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	3	MLH1, LRRFIP2, MSH2

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)
MLH1	0	—
LRRFIP2	0	—
MSH2	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.