CDH1-related diffuse gastric and lobular breast cancer syndrome

Summary

CDH1-related diffuse gastric and lobular breast cancer syndrome (MONDO:0100488) is a cancer caused by CDH1 (GenCC Definitive), with 1 cohort gene (1 CIViC-evidence somatic driver; 385 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Causal gene: CDH1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 385

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	CDH1-related diffuse gastric and lobular breast cancer syndrome
Mondo ID	MONDO:0100488
OMIM	137215
GARD	0026244
Is cancer (heuristic)	yes

Also known as: DGLBC · diffuse gastric and lobular breast cancer syndrome · gastric cancer, familial diffuse breast cancer, lobular · gastric cancer, hereditary diffuse · HDGC · LBC

Data availability: 385 ClinVar variants · 330 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 › hereditary neoplastic syndrome › CDH1-related diffuse gastric and lobular breast cancer syndrome

Related subtypes (116): mosaic variegated aneuploidy syndrome, tuberous sclerosis, hereditary breast ovarian cancer syndrome, hereditary multiple osteochondromas, nevoid basal cell carcinoma syndrome, leukemia, chronic lymphocytic, susceptibility to, 2, blue rubber bleb nevus, cherubism, Beckwith-Wiedemann syndrome, multiple self-healing squamous epithelioma, erythroleukemia, familial, susceptibility to, goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, hyperparathyroidism 2 with jaw tumors, Kaposi sarcoma, susceptibility to, hereditary leiomyomatosis and renal cell cancer, susceptibility to uveal melanoma, melanoma and neural system tumor syndrome, nasopharyngeal carcinoma, susceptibility to, 2, WAGR syndrome, neuroblastoma, susceptibility to, 1, Rothmund-Thomson syndrome, mismatch repair cancer syndrome 1, Wiskott-Aldrich syndrome, N syndrome, hereditary thrombocytopenia and hematologic cancer predisposition syndrome, prostate cancer/brain cancer susceptibility, Brooke-Spiegler syndrome, pancreatic cancer, susceptibility to, 1, Carney-Stratakis syndrome, nasopharyngeal carcinoma, susceptibility to, 1, ovarian cancer, susceptibility to, 1, colorectal cancer, susceptibility to, 1, lung cancer susceptibility 1, leukemia, chronic lymphocytic, susceptibility to, 1, Kostmann syndrome, colorectal cancer, susceptibility to, 2, colorectal cancer, susceptibility to, 3, colorectal cancer, susceptibility to, 5, colorectal cancer, susceptibility to, 6, colorectal cancer, susceptibility to, 7, leukemia, chronic lymphocytic, susceptibility to, 3, leukemia, chronic lymphocytic, susceptibility to, 4, leukemia, chronic lymphocytic, susceptibility to, 5, lung cancer susceptibility 3, colorectal cancer, susceptibility to, 8, colorectal cancer, susceptibility to, 9, colorectal cancer, susceptibility to, 10, colorectal cancer, susceptibility to, 11, lung cancer susceptibility 4, neuroblastoma, susceptibility to, 3, neuroblastoma, susceptibility to, 4, neuroblastoma, susceptibility to, 5, neuroblastoma, susceptibility to, 6, leukemia, acute lymphocytic, susceptibility to, 1, leukemia, acute lymphocytic, susceptibility to, 2, lung cancer susceptibility 5, BAP1-related tumor predisposition syndrome, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Maffucci syndrome, basal cell carcinoma, susceptibility to, 7, colorectal cancer, susceptibility to, 12, leukemia, acute lymphoblastic, susceptibility to, 3, cholangiocarcinoma, susceptibility to, progeroid features-hepatocellular carcinoma predisposition syndrome, neuroblastoma, susceptibility to, 7, DDX41-related hematologic malignancy predisposition syndrome, nasopharyngeal carcinoma, susceptibility to, 3, familial isolated hyperparathyroidism, intestinal polyposis syndrome, dyskeratosis congenita, familial rhabdoid tumor, multiple endocrine neoplasia, hereditary pheochromocytoma-paraganglioma, PTEN hamartoma tumor syndrome, familial multiple fibrofolliculoma, hereditary retinoblastoma, familial atypical multiple mole melanoma syndrome, hereditary nonpolyposis colon cancer, Li-Fraumeni syndrome, Cobb syndrome, neurofibromatosis, susceptibility to familial cutaneous melanoma, pancreatic cancer, susceptibility to, 5, leukemia, acute myeloid, susceptibility to, diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, glioma susceptibility, hemangioma, capillary infantile, susceptibility to, NTHL1-deficiency tumor predisposition syndrome, SAMD9-related spectrum and myeloid neoplasm risk, neuroblastoma, susceptibility to, 2, BARD1-related cancer predisposition, BRCA1-related cancer predisposition, BRCA2-related cancer predisposition, ATM-related cancer predisposition, CHEK2-related cancer predisposition, PALB2-related cancer predisposition, RAD51C-related cancer predisposition, RAD51D-related cancer predisposition, Li-fraumeni-like syndrome, breast cancer, familial, susceptibility to, 1, breast cancer, familial, susceptibility to, 2, breast cancer, familial, susceptibility to, 3, colorectal cancer, susceptibility to, 4, colorectal cancer, susceptibility to, on chromosome 15, ovarian cancer, familial, susceptibility to, 1, ovarian cancer, familial, susceptibility to, 2, ovarian cancer, familial, susceptibility to, 3, inherited hematologic cancer-predisposing syndrome, mosaic neurofibromatosis/schwannomatosis, tumor predisposition syndrome 2, prostate cancer, hereditary, X-linked 3, follicular lymphoma, susceptibility to, GPR161-related medulloblastoma predisposition, SAMD9L-related spectrum and myeloid neoplasm risk, HAVCR2-related cancer predisposition, EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition

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

385 retrieved; paginated sample, class counts are floors:

134 pathogenic, 71 likely benign, 61 uncertain significance, 60 benign, 24 likely pathogenic, 18 conflicting classifications of pathogenicity, 14 benign/likely benign, 2 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
12234	NM_004360.5(CDH1):c.781G>T (p.Glu261Ter)	CDH1	Pathogenic	reviewed by expert panel
12237	NM_004360.5(CDH1):c.2095C>T (p.Gln699Ter)	CDH1	Pathogenic	reviewed by expert panel
12239	NM_004360.5(CDH1):c.59G>A (p.Trp20Ter)	CDH1	Pathogenic	reviewed by expert panel
12240	NM_004360.5(CDH1):c.70G>T (p.Glu24Ter)	CDH1	Pathogenic	reviewed by expert panel
12241	NM_004360.5(CDH1):c.1792C>T (p.Arg598Ter)	CDH1	Pathogenic	reviewed by expert panel
127915	NM_004360.5(CDH1):c.1565+1G>A	CDH1	Pathogenic	reviewed by expert panel
1292056	NM_004360.5(CDH1):c.2076_2077del (p.Gly693fs)	CDH1	Pathogenic	reviewed by expert panel
1292057	NM_004360.5(CDH1):c.2T>A (p.Met1Lys)	CDH1	Pathogenic	reviewed by expert panel
132709	NM_004360.5(CDH1):c.715G>A (p.Gly239Arg)	CDH1	Pathogenic	reviewed by expert panel
136055	NM_004360.5(CDH1):c.1003C>T (p.Arg335Ter)	CDH1	Pathogenic	reviewed by expert panel
136065	NM_004360.5(CDH1):c.2287G>T (p.Glu763Ter)	CDH1	Pathogenic	reviewed by expert panel
140781	NM_004360.5(CDH1):c.2064_2065del (p.Cys688_Glu689delinsTer)	CDH1	Pathogenic	reviewed by expert panel
140803	NM_004360.5(CDH1):c.521dup (p.Asn174fs)	CDH1	Pathogenic	reviewed by expert panel
141206	NM_004360.5(CDH1):c.1565+1G>T	CDH1	Pathogenic	reviewed by expert panel
142826	NM_004360.5(CDH1):c.1921C>T (p.Gln641Ter)	CDH1	Pathogenic	reviewed by expert panel
142888	NM_004360.5(CDH1):c.1147C>T (p.Gln383Ter)	CDH1	Pathogenic	reviewed by expert panel
156374	NM_004360.5(CDH1):c.1023T>G (p.Tyr341Ter)	CDH1	Pathogenic	reviewed by expert panel
156496	NM_004360.5(CDH1):c.187C>T (p.Arg63Ter)	CDH1	Pathogenic	reviewed by expert panel
156497	NM_004360.5(CDH1):c.2398del (p.Arg800fs)	CDH1	Pathogenic	reviewed by expert panel
156499	NM_004360.5(CDH1):c.1137G>A (p.Thr379=)	CDH1	Pathogenic	reviewed by expert panel
182376	NM_004360.5(CDH1):c.1979dup (p.Gly661_Asp662insTer)	CDH1	Pathogenic	reviewed by expert panel
182393	NM_004360.5(CDH1):c.707C>A (p.Ser236Ter)	CDH1	Pathogenic	reviewed by expert panel
183727	NM_004360.5(CDH1):c.1009_1010del (p.Ser337Phefs)	CDH1	Pathogenic	reviewed by expert panel
183750	NM_004360.5(CDH1):c.76G>T (p.Glu26Ter)	CDH1	Pathogenic	reviewed by expert panel
185252	NM_004360.5(CDH1):c.1999del (p.Leu667fs)	CDH1	Pathogenic	reviewed by expert panel
185408	NM_004360.5(CDH1):c.202del (p.Tyr68fs)	CDH1	Pathogenic	reviewed by expert panel
187239	NM_004360.5(CDH1):c.60G>A (p.Trp20Ter)	CDH1	Pathogenic	reviewed by expert panel
187464	NM_004360.5(CDH1):c.2430del (p.Phe810fs)	CDH1	Pathogenic	reviewed by expert panel
220776	NM_004360.5(CDH1):c.504del (p.Gly169fs)	CDH1	Pathogenic	reviewed by expert panel
224528	NM_004360.5(CDH1):c.1064del (p.Gly354_Leu355insTer)	CDH1	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
CDH1	LoF	BLCA,BRCA,CSCC,DLBCLNOS,ESCA,STAD	CIViC #888

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
CDH1	Definitive	Autosomal dominant	hereditary breast carcinoma	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CDH1	Orphanet:1331	Familial prostate cancer
CDH1	Orphanet:199306	Cleft lip/palate
CDH1	Orphanet:1997	Blepharo-cheilo-odontic syndrome
CDH1	Orphanet:227535	Hereditary breast cancer
CDH1	Orphanet:26106	Hereditary diffuse gastric cancer

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
CDH1	HGNC:1748	ENSG00000039068	P12830	Cadherin-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDH1	Cadherin-1	Cadherins are calcium-dependent cell adhesion proteins.

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)
CDH1	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin_pro_dom

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
esophagus squamous epithelium	1
gingival epithelium	1
jejunal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDH1	245	broad	marker	jejunal mucosa, esophagus squamous epithelium, gingival epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDH1	8,738

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CDH1	P12830	22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 44. 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
Epithelial-Mesenchymal Transition (EMT) during gastrulation	1	1427.5×	0.006	CDH1
InlA-mediated entry of Listeria monocytogenes into host cells	1	1268.9×	0.006	CDH1
Apoptotic cleavage of cell adhesion proteins	1	1038.2×	0.006	CDH1
Listeria monocytogenes entry into host cells	1	1038.2×	0.006	CDH1
Regulation of CDH1 mRNA translation by microRNAs	1	1038.2×	0.006	CDH1
Regulation of CDH1 Function	1	951.7×	0.006	CDH1
Positive Regulation of CDH1 Gene Transcription	1	951.7×	0.006	CDH1
Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition	1	878.5×	0.006	CDH1
Developmental Lineage of Mammary Stem Cells	1	761.3×	0.006	CDH1
Formation of definitive endoderm	1	713.8×	0.006	CDH1
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	543.8×	0.006	CDH1
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	1	496.5×	0.006	CDH1
Apoptotic cleavage of cellular proteins	1	475.8×	0.006	CDH1
Apoptotic execution phase	1	475.8×	0.006	CDH1
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	456.8×	0.006	CDH1
RHO GTPases activate IQGAPs	1	346.1×	0.007	CDH1
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	1	335.9×	0.007	CDH1
Bacterial Infection Pathways	1	335.9×	0.007	CDH1
Gastrulation	1	259.6×	0.008	CDH1
Adherens junctions interactions	1	248.3×	0.008	CDH1
Cell-cell junction organization	1	248.3×	0.008	CDH1
Degradation of CDH1	1	196.9×	0.010	CDH1
Cell junction organization	1	187.2×	0.010	CDH1
MITF-M-dependent gene expression	1	181.3×	0.010	CDH1
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.010	CDH1
Apoptosis	1	167.9×	0.010	CDH1
Activation of STAT3 by cadherin engagement	1	163.1×	0.010	CDH1
Programmed Cell Death	1	146.4×	0.011	CDH1
Cell-Cell communication	1	137.6×	0.011	CDH1
Integrin cell surface interactions	1	134.3×	0.011	CDH1

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
response to heparin	1	5617.3×	0.002	CDH1
regulation of protein catabolic process at postsynapse, modulating synaptic transmission	1	4213.0×	0.002	CDH1
cellular response to indole-3-methanol	1	3370.4×	0.002	CDH1
response to Gram-positive bacterium	1	2808.7×	0.002	CDH1
desmosome assembly	1	2407.4×	0.002	CDH1
positive regulation of protein localization	1	1404.3×	0.003	CDH1
cellular response to lithium ion	1	1123.5×	0.003	CDH1
negative regulation of cell-cell adhesion	1	991.3×	0.003	CDH1
negative regulation of axon extension	1	732.7×	0.004	CDH1
pituitary gland development	1	648.1×	0.004	CDH1
adherens junction organization	1	510.7×	0.004	CDH1
calcium-dependent cell-cell adhesion	1	481.5×	0.004	CDH1
cell-cell junction assembly	1	443.5×	0.004	CDH1
positive regulation of protein import into nucleus	1	421.3×	0.004	CDH1
cell-cell adhesion mediated by cadherin	1	411.0×	0.004	CDH1
synapse assembly	1	230.8×	0.007	CDH1
response to toxic substance	1	210.7×	0.008	CDH1
cell morphogenesis	1	157.5×	0.010	CDH1
homophilic cell-cell adhesion	1	140.4×	0.010	CDH1
neuron projection development	1	122.1×	0.011	CDH1
negative regulation of cell migration	1	111.6×	0.011	CDH1
protein localization to plasma membrane	1	108.7×	0.011	CDH1
cell-cell adhesion	1	101.5×	0.012	CDH1
regulation of gene expression	1	83.4×	0.013	CDH1
response to xenobiotic stimulus	1	69.1×	0.016	CDH1
cell migration	1	61.5×	0.017	CDH1
positive regulation of DNA-templated transcription	1	27.9×	0.036	CDH1

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
CDH1	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
CDH1	18	Binding:18

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	CDH1

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)
CDH1	18	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.