APC

APC regulator of WNT signaling pathway, the group of Armadillo repeat containing|Protein phosphatase 1 regulatory subunits

Basic information

Region (hg38): 5:112707518-112846239

Links

ENSG00000134982 ∙ NCBI:324 ∙ OMIM:611731 ∙ HGNC:583 ∙ Uniprot:P25054 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• familial adenomatous polyposis 1 (Moderate), mode of inheritance: AD
• sarcoma (Moderate), mode of inheritance: AD
• desmoid tumor (Strong), mode of inheritance: AD
• familial adenomatous polyposis 1 (Strong), mode of inheritance: AD
• familial adenomatous polyposis 1 (Definitive), mode of inheritance: AD
• Cenani-Lenz syndactyly syndrome (Supportive), mode of inheritance: AR
• Turcot syndrome with polyposis (Supportive), mode of inheritance: AD
• APC-related attenuated familial adenomatous polyposis (Supportive), mode of inheritance: AD
• gastric adenocarcinoma and proximal polyposis of the stomach (Supportive), mode of inheritance: AD
• desmoid tumor (Definitive), mode of inheritance: AD
• familial adenomatous polyposis 1 (Strong), mode of inheritance: AD
• gastric adenocarcinoma and proximal polyposis of the stomach (Strong), mode of inheritance: AD
• gastric adenocarcinoma and proximal polyposis of the stomach (Definitive), mode of inheritance: AD
• classic or attenuated familial adenomatous polyposis (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Familial adenomatous polyposis 1; Desmoid disease, hereditary; Gastric adenocarcinoma and proximal polyposis of the stomach	AD	Oncologic	Depending on the specific APC-related condition, individuals may be at risk for a variety of neoplasms, and surveillance (including for gastric adenocarcinoma, thyroid disease, duodenal and colonic neoplasms, and hepatoblastoma, the latter with ultrasound and serum AFP measurement, as well as for other types of neoplastic manifestations) may allow early detection and management, which may reduce morbidity and mortality; In FAP, medical management (with NSAIDs) have been reported to result in adenoma regression and decreased polyp number; Colectomy is indicated when a specific numeric/pathologic adenomatous burden has been reached; Prophylactic gastrectomy has been described in Gastric adenocarcinoma and proximal polyposis of the stomach	Dental; Dermatologic; Musculoskeletal; Oncologic; Ophthalmologic	14902760; 14933371; 13707264; 13891268; 13946545; 14136536; 5644968; 5660317; 5660235; 5443116; 4739325; 4853059; 1111674; 856075; 880737; 739523; 758668; 7446647; 7296952; 7067564; 6121129; 7172944; 6887943; 6129922; 6690356; 2435780; 2827474; 3033343; 3821797; 3800608; 2848134; 2848134; 3338026; 2896968; 3354603; 2156161; 1658283; 1651174; 1651563; 1324223; 1317264; 1329510; 1314729; 1544113; 1316610; 1316858; 8281160; 8276387; 8244107; 8105087; 8385741; 8037405; 8064829; 7661930; 8826936; 8940264; 8940262; 8968744; 9215849; 9585611; 10504375; 10077730; 10782927; 10815155; 10874062; 11932472; 12621137; 17135589; 18395100; 19793053; 20301519; 20400027; 20105204; 21813476; 22305464; 22773231; 22886683; 27087319; 27343414; 31409086; 33242120
Gastric adenocarcinoma and proximal polyposis of the stomach results from variants in the APC gene promoter 1B

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the APC gene.

• Familial adenomatous polyposis 1 (1569 variants)
• Hereditary cancer-predisposing syndrome (634 variants)
• not provided (288 variants)
• Familial multiple polyposis syndrome (76 variants)
• Carcinoma of colon (48 variants)
• Classic or attenuated familial adenomatous polyposis (23 variants)
• APC-related disorder (14 variants)
• Colorectal cancer (11 variants)
• not specified (9 variants)
• Neoplasm of the large intestine (9 variants)
• Gardner syndrome (7 variants)
• Gastric cancer (7 variants)
• 6 conditions (5 variants)
• Desmoid disease, hereditary (3 variants)
• Colorectal cancer, susceptibility to (3 variants)
• APC-Associated Polyposis Disorders (3 variants)
• Neoplasm of stomach;Familial adenomatous polyposis 1;Desmoid disease, hereditary;Hepatocellular carcinoma;Carcinoma of colon (2 variants)
• Brain tumor-polyposis syndrome 2 (2 variants)
• Familial colorectal cancer (2 variants)
• Desmoid disease, hereditary;Carcinoma of colon;Hepatocellular carcinoma;Familial adenomatous polyposis 1;Neoplasm of stomach (1 variants)
• Periampullary adenoma (1 variants)
• Gastric adenocarcinoma and proximal polyposis of the stomach (1 variants)
• Carcinoma of colon;Hepatocellular carcinoma;Familial adenomatous polyposis 1;Neoplasm of stomach;Desmoid disease, hereditary (1 variants)
• Adenomatous colonic polyposis (1 variants)
• Carcinoma of colon;Desmoid disease, hereditary;Familial adenomatous polyposis 1;Neoplasm of stomach;Hepatocellular carcinoma (1 variants)
• Lung adenocarcinoma (1 variants)
• Carcinoma of colon;Familial adenomatous polyposis 1;Neoplasm of stomach;Hepatocellular carcinoma;Desmoid disease, hereditary (1 variants)
• Craniopharyngioma (1 variants)
• Familial adenomatous polyposis 1;Gastric adenocarcinoma and proximal polyposis of the stomach;APC-related attenuated familial adenomatous polyposis (1 variants)
• Atypical endometrial hyperplasia (1 variants)
• Hepatoblastoma (1 variants)
• Colon adenocarcinoma (1 variants)
• Colonic neoplasm (1 variants)
• Desmoid tumor (1 variants)
• Duodenal polyposis;Hyperplastic colonic polyposis;Gastric polyposis;Adenomatous colonic polyposis;Intestinal polyp (1 variants)
• Adenomatous polyposis coli with congenital cholesteatoma (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the APC gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			17	2281	222	2520
missense	8	10	6213	44	13	6288
nonsense	518	58	6			582
start loss			2			2
frameshift	1267	165	12			1444
inframe indel			165	1	1	167
splice donor/acceptor (+/-2bp)	29	81	5	1		116
splice region	19	27	62	109	4	221
non coding	5	11	65	378	81	540
Total	1827	325	6485	2705	317

Highest pathogenic variant AF is 0.0000131

Variants in APC

This is a list of pathogenic ClinVar variants found in the APC region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
5-112707519-C-G		Familial adenomatous polyposis 1	Uncertain significance (Sep 01, 2022)
5-112707519-C-T		Familial adenomatous polyposis 1	Likely benign (Jan 09, 2024)
5-112707521-A-C		Familial adenomatous polyposis 1	Uncertain significance (Jul 27, 2023)
5-112707521-A-G		Familial adenomatous polyposis 1	Uncertain significance (Oct 15, 2023)
5-112707521-A-T		Familial adenomatous polyposis 1	Uncertain significance (Nov 22, 2022)
5-112707522-C-T		Familial adenomatous polyposis 1	Uncertain significance (Feb 24, 2022)
5-112707523-A-C		Hereditary cancer-predisposing syndrome	Pathogenic (Jan 02, 2020)
5-112707525-G-A		Hereditary cancer-predisposing syndrome • Familial adenomatous polyposis 1	Uncertain significance (Jul 17, 2023)
5-112707525-G-C		Familial adenomatous polyposis 1	Uncertain significance (Dec 21, 2022)
5-112707526-A-G		Gastric adenocarcinoma and proximal polyposis of the stomach • Hereditary cancer-predisposing syndrome • Familial adenomatous polyposis 1	Likely pathogenic (Oct 24, 2023)
5-112707526-A-T		Familial adenomatous polyposis 1	Pathogenic (Jul 12, 2016)
5-112707526-AT-TAGCAAGGG		Familial adenomatous polyposis 1 • Hereditary cancer-predisposing syndrome	Likely pathogenic (Sep 21, 2023)
5-112707527-T-A		Familial adenomatous polyposis 1	Uncertain significance (Nov 05, 2023)
5-112707527-T-C		Familial adenomatous polyposis 1 • Hereditary cancer-predisposing syndrome • Gastric adenocarcinoma and proximal polyposis of the stomach	Pathogenic/Likely pathogenic (Jan 19, 2024)
5-112707527-T-G		Hereditary cancer-predisposing syndrome	Likely pathogenic (Jun 24, 2024)
5-112707528-G-A		Familial adenomatous polyposis 1 • Hereditary cancer-predisposing syndrome • Periampullary adenoma	Pathogenic/Likely pathogenic (Mar 14, 2024)
5-112707529-G-A		Familial adenomatous polyposis 1	Uncertain significance (Nov 07, 2022)
5-112707530-C-A		Familial adenomatous polyposis 1 • Classic or attenuated familial adenomatous polyposis	Uncertain significance (Apr 03, 2023)
5-112707530-C-T		Hereditary cancer-predisposing syndrome • not specified • Familial adenomatous polyposis 1	Conflicting classifications of pathogenicity (Jan 25, 2024)
5-112707531-G-A		Hereditary cancer-predisposing syndrome • Familial adenomatous polyposis 1 • Classic or attenuated familial adenomatous polyposis	Uncertain significance (Dec 18, 2023)
5-112707532-G-A		Familial adenomatous polyposis 1	Uncertain significance (Apr 26, 2023)
5-112707532-G-T		Familial adenomatous polyposis 1	Uncertain significance (Sep 01, 2021)
5-112707533-A-C		Familial adenomatous polyposis 1	Uncertain significance (May 02, 2019)
5-112707534-G-A		Familial adenomatous polyposis 1	Uncertain significance (Oct 09, 2023)
5-112707534-G-C		Familial adenomatous polyposis 1	Uncertain significance (Aug 01, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
APC	protein_coding	protein_coding	ENST00000457016	15	138742

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	5.56e-11	125710	0	38	125748	0.000151

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.168	1436	1.45e+3	0.988	0.0000754	18618
Missense in Polyphen		499	573.43	0.8702		7508
Synonymous	-1.98	564	507	1.11	0.0000253	5556
Loss of Function	8.90	11	113	0.0972	0.00000712	1436

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000475	0.000474
Ashkenazi Jewish	0.000109	0.0000992
East Asian	0.0000544	0.0000544
Finnish	0.000277	0.000231
European (Non-Finnish)	0.000124	0.000123
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000654	0.0000653
Other	0.000327	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Tumor suppressor. Promotes rapid degradation of CTNNB1 and participates in Wnt signaling as a negative regulator. APC activity is correlated with its phosphorylation state. Activates the GEF activity of SPATA13 and ARHGEF4. Plays a role in hepatocyte growth factor (HGF)-induced cell migration. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells. Acts as a mediator of ERBB2-dependent stabilization of microtubules at the cell cortex. It is required for the localization of MACF1 to the cell membrane and this localization of MACF1 is critical for its function in microtubule stabilization. {ECO:0000269|PubMed:10947987, ECO:0000269|PubMed:17599059, ECO:0000269|PubMed:19151759, ECO:0000269|PubMed:19893577, ECO:0000269|PubMed:20937854}.
• Disease: DISEASE: Familial adenomatous polyposis (FAP) [MIM:175100]: A cancer predisposition syndrome characterized by adenomatous polyps of the colon and rectum, but also of upper gastrointestinal tract (ampullary, duodenal and gastric adenomas). This is a viciously premalignant disease with one or more polyps progressing through dysplasia to malignancy in untreated gene carriers with a median age at diagnosis of 40 years. {ECO:0000269|PubMed:10470088, ECO:0000269|PubMed:1338691, ECO:0000269|PubMed:1338764, ECO:0000269|PubMed:1338904, ECO:0000269|PubMed:1651563, ECO:0000269|PubMed:21643010, ECO:0000269|PubMed:27217144, ECO:0000269|PubMed:7661930, ECO:0000269|PubMed:7833149, ECO:0000269|PubMed:7833931, ECO:0000269|PubMed:8990002}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hereditary desmoid disease (HDD) [MIM:135290]: Autosomal dominant trait with 100% penetrance and possible variable expression among affected relatives. HDD patients show multifocal fibromatosis of the paraspinal muscles, breast, occiput, arms, lower ribs, abdominal wall, and mesentery. Desmoid tumors appears also as a complication of familial adenomatous polyposis. {ECO:0000269|PubMed:10782927, ECO:0000269|PubMed:8940264}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Medulloblastoma (MDB) [MIM:155255]: Malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children. {ECO:0000269|PubMed:10666372}. Note=The gene represented in this entry may be involved in disease pathogenesis.; DISEASE: Gastric cancer (GASC) [MIM:613659]: A malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions, resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease. Note=The gene represented in this entry may be involved in disease pathogenesis.; DISEASE: Hepatocellular carcinoma (HCC) [MIM:114550]: A primary malignant neoplasm of epithelial liver cells. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. Note=The gene represented in this entry may be involved in disease pathogenesis.
• Pathway: Gastric cancer - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Breast cancer - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Regulation of actin cytoskeleton - Homo sapiens (human);Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);Basal cell carcinoma - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Hippo signaling pathway - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Wnt signaling pathway - Homo sapiens (human);Endometrial cancer - Homo sapiens (human);Colorectal cancer - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Cell Cycle;Angiogenesis overview;Regulation of Microtubule Cytoskeleton;Gastric Cancer Network 1;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;Endoderm Differentiation;Extracellular vesicle-mediated signaling in recipient cells;Copper homeostasis;Wnt Signaling Pathway;Wnt-beta-catenin Signaling Pathway in Leukemia;Regulation of Wnt-B-catenin Signaling by Small Molecule Compounds;Association Between Physico-Chemical Features and Toxicity Associated Pathways;ESC Pluripotency Pathways;Wnt Signaling Pathway and Pluripotency;Endometrial cancer;Chromosomal and microsatellite instability in colorectal cancer;Wnt Signaling Pathway;Regulation of Actin Cytoskeleton;DNA Damage Response (only ATM dependent);Degradation of beta-catenin by the destruction complex;Signaling by WNT;Signal Transduction;Post-translational protein modification;Metabolism of proteins;Apoptotic cleavage of cellular proteins;Apoptotic execution phase;Apoptosis;Programmed Cell Death;Disassembly of the destruction complex and recruitment of AXIN to the membrane;Ovarian tumor domain proteases;Deubiquitination;Beta-catenin phosphorylation cascade;Direct p53 effectors;Wnt;Wnt Canonical;Regulation of nuclear beta catenin signaling and target gene transcription;Degradation of beta catenin;Regulation of CDC42 activity;CDC42 signaling events;Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met);TCF dependent signaling in response to WNT;Canonical Wnt signaling pathway;Wnt Mammals;Presenilin action in Notch and Wnt signaling (Consensus)

Recessive Scores

• pRec: 0.571

Intolerance Scores

• loftool: 0.00386
• rvis_EVS: -2.52
• rvis_percentile_EVS: 0.9

Haploinsufficiency Scores

• pHI: 0.532
• hipred: Y
• hipred_score: 0.731
• ghis: 0.625

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.859

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Apc
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; craniofacial phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; immune system phenotype; renal/urinary system phenotype; skeleton phenotype; digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hearing/vestibular/ear phenotype; limbs/digits/tail phenotype; vision/eye phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; reproductive system phenotype; pigmentation phenotype; neoplasm; embryo phenotype

Zebrafish Information Network

• Gene name: apc
• Affected structure: hepatocyte
• Phenotype tag: abnormal
• Phenotype quality: increased amount

Gene ontology

• Biological process: mitotic cytokinesis;cell fate specification;cellular response to DNA damage stimulus;negative regulation of microtubule depolymerization;cell cycle arrest;mitotic spindle assembly checkpoint;cell adhesion;pattern specification process;negative regulation of cell population proliferation;insulin receptor signaling pathway;positive regulation of cell death;Wnt signaling pathway;cell migration;protein deubiquitination;positive regulation of cell migration;positive regulation of pseudopodium assembly;regulation of microtubule-based process;positive regulation of apoptotic process;regulation of cell differentiation;positive regulation of protein catabolic process;negative regulation of cyclin-dependent protein serine/threonine kinase activity;protein homooligomerization;regulation of attachment of spindle microtubules to kinetochore;protein-containing complex assembly;bicellular tight junction assembly;negative regulation of canonical Wnt signaling pathway;positive regulation of cold-induced thermogenesis;positive regulation of protein localization to centrosome;beta-catenin destruction complex assembly;beta-catenin destruction complex disassembly
• Cellular component: kinetochore;nucleus;nucleoplasm;cytoplasm;centrosome;cytosol;microtubule;cytoplasmic microtubule;plasma membrane;cell-cell adherens junction;bicellular tight junction;lateral plasma membrane;catenin complex;lamellipodium;beta-catenin destruction complex;ruffle membrane;perinuclear region of cytoplasm;Wnt signalosome
• Molecular function: protein binding;beta-catenin binding;microtubule binding;protein kinase regulator activity;protein kinase binding;ubiquitin protein ligase binding;identical protein binding;gamma-catenin binding;cadherin binding;microtubule plus-end binding;dynein complex binding