Lynch syndrome 8

Summary

Lynch syndrome 8 (MONDO:0013196) is a disease caused by EPCAM (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: EPCAM (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 55

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Lynch syndrome 8
Mondo ID	MONDO:0013196
MeSH	C567685
OMIM	613244
DOID	DOID:0070270
UMLS	C2750471
MedGen	412966
GARD	0015638
Is cancer (heuristic)	no

Also known as: colorectal cancer, hereditary nonpolyposis, type 8 · EPCAM hereditary nonpolyposis colon cancer · hereditary nonpolyposis colon cancer caused by mutation in EPCAM · HNPCC8

Data availability: 55 ClinVar variants · 4 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 8

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

55 retrieved; paginated sample, class counts are floors:

25 uncertain significance, 9 benign/likely benign, 7 benign, 5 pathogenic, 3 likely benign, 2 conflicting classifications of pathogenicity, 2 likely pathogenic, 1 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
12775	NC_000002.12:g.47383704_47388612del	EPCAM	Pathogenic	no assertion criteria provided
12776	NR_030286.1(MIR559):n.278_23134del	EPCAM	Pathogenic	no assertion criteria provided
157603	NM_002354.3(EPCAM):c.556-14A>G	EPCAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3779618	NM_002354.3(EPCAM):c.556-1_657+289del	EPCAM	Pathogenic	criteria provided, single submitter
3780848	NM_002354.3(EPCAM):c.556_945del390 (p.Tyr186_Ter315del)	EPCAM	Pathogenic	criteria provided, single submitter
3780849	NM_002354.3(EPCAM):c.904-1_*1del	EPCAM	Pathogenic	criteria provided, single submitter
3336801	NC_000002.12:g.(47369582_47373462)(47386613?)del	EPCAM	Likely pathogenic	criteria provided, single submitter
3336805	NC_000002.12:g.(47369582_47373462)(47386896?)del	EPCAM	Likely pathogenic	criteria provided, single submitter
1788402	NM_002354.3(EPCAM):c.224G>A (p.Gly75Asp)	EPCAM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215813	NM_002354.3(EPCAM):c.304A>G (p.Ser102Gly)	EPCAM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1049938	NM_002354.3(EPCAM):c.-2_77del (p.Met1fs)	EPCAM	Uncertain significance	no assertion criteria provided
1320282	NM_002354.3(EPCAM):c.849TGT[1] (p.Val285del)	EPCAM	Uncertain significance	criteria provided, single submitter
136018	NM_002354.3(EPCAM):c.232C>G (p.Leu78Val)	EPCAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
136022	NM_002354.3(EPCAM):c.466C>T (p.Pro156Ser)	EPCAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
136026	NM_002354.3(EPCAM):c.574A>T (p.Thr192Ser)	EPCAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
136027	NM_002354.3(EPCAM):c.577A>G (p.Ile193Val)	EPCAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
1675779	NM_002354.3(EPCAM):c.28G>C (p.Gly10Arg)	EPCAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
1691520	NM_002354.3(EPCAM):c.344T>A (p.Met115Lys)	EPCAM	Uncertain significance	criteria provided, single submitter
1691528	NM_002354.3(EPCAM):c.64G>A (p.Ala22Thr)	EPCAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
1793058	NM_002354.3(EPCAM):c.255A>T (p.Glu85Asp)	EPCAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
1801503	NM_002354.3(EPCAM):c.214G>A (p.Glu72Lys)	EPCAM	Uncertain significance	criteria provided, single submitter
188106	NM_002354.3(EPCAM):c.50C>T (p.Thr17Met)	EPCAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
188370	NM_002354.3(EPCAM):c.161A>G (p.Gln54Arg)	EPCAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
216562	NM_002354.3(EPCAM):c.859-3C>G	EPCAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
239119	NM_002354.3(EPCAM):c.111C>G (p.Asn37Lys)	EPCAM	Uncertain significance	criteria provided, single submitter
239124	NM_002354.3(EPCAM):c.179C>T (p.Ser60Leu)	EPCAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
239136	NM_002354.3(EPCAM):c.616G>A (p.Asp206Asn)	EPCAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
2431898	NM_002354.3(EPCAM):c.413G>A (p.Arg138Gln)	EPCAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
2444863	NM_002354.3(EPCAM):c.849T>G (p.Ile283Met)	EPCAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
2627067	NM_002354.3(EPCAM):c.527T>C (p.Leu176Pro)	EPCAM	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 2 · 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
EPCAM	Definitive	Autosomal dominant	Lynch syndrome 8	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EPCAM	Orphanet:144	Lynch syndrome
EPCAM	Orphanet:92050	Congenital tufting enteropathy

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
EPCAM	HGNC:11529	ENSG00000119888	P16422	Epithelial cell adhesion molecule	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EPCAM	Epithelial cell adhesion molecule	May act as a physical homophilic interaction molecule between intestinal epithelial cells (IECs) and intraepithelial lymphocytes (IELs) at the mucosal epithelium for providing immunological barrier as a first line of defense against mucosa…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EPCAM	Enzyme (other)	yes	2.4.1.37	Thyroglobulin_1, Thyroglobulin_1_sf, EpCAM_N

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
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EPCAM	253	broad	marker	jejunal mucosa, colonic mucosa, mucosa of sigmoid colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EPCAM	3,359

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EPCAM	P16422	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Developmental Lineage of Mammary Stem Cells	1	761.3×	0.003	EPCAM
Developmental Lineage of Mammary Gland Alveolar Cells	1	634.4×	0.003	EPCAM
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	543.8×	0.003	EPCAM
Attachment of bacteria to epithelial cells	1	496.5×	0.003	EPCAM
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	456.8×	0.003	EPCAM
Cell surface interactions at the vascular wall	1	95.2×	0.011	EPCAM

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
negative regulation of cell-cell adhesion mediated by cadherin	1	1532.0×	0.004	EPCAM
signal transduction involved in regulation of gene expression	1	702.2×	0.004	EPCAM
positive regulation of stem cell proliferation	1	526.6×	0.004	EPCAM
ureteric bud development	1	455.5×	0.004	EPCAM
stem cell differentiation	1	300.9×	0.005	EPCAM
positive regulation of cell population proliferation	1	33.6×	0.035	EPCAM
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	EPCAM

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
EPCAM	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
EPCAM	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EPCAM	2.4.1.37, 2.4.1.40	fucosylgalactoside 3-alpha-galactosyltransferase, glycoprotein-fucosylgalactoside alpha-N-acetylgalactosaminyltransferase

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).

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	1	EPCAM
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
EPCAM	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.