APC
protein-codingAPC regulator of WNT signaling pathway, the group of Armadillo repeat containing|Protein phosphatase 1 regulatory subunits
Gene summary
This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~138.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0021056
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007608
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0017790
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0005089
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0008931
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0021057
Submitter: ClinGen
APC variants have been reported for over 30 years in relation to autosomal dominant Familial Adenomatous Polyposis (FAP) (PMIDs: 1651174, 1651562, 1651563), with subsequent recognition of classical (cFAP) and attenuated (aFAP) phenotypes. The cFAP patients develop more than 100 adenomatous colon polyps, while aFAP is a less severe form of familial polyposis, which is characterized by a lower number of adenomatous polyps (fewer than 100). Individuals with aFAP are also likely to develop polyps and colorectal cancer later in life than cFAP patients. cFAP is usually caused by germline mutations in the APC gene between codons 178 and 1580. However, germline mutations associated with aFAP tend to cluster in specific regions of the APC gene the 5′ end (codons 1–177, exons 1–4); the 3′ end (distal to codon 1580); and the alternatively spliced region of exon 9 (codons 311–408). Colonic polyp number varied greatly among aFAP patients and 5′ mutants generally had more polyps than other aFAP patients (PMID: 16461775). Although there are some differences between cFAP and aFAP, we found no difference in inheritance pattern and similarities in phenotypes and molecular mechanisms (both caused by loss of function alleles), per criteria outlined by the ClinGen Lumping and Splitting Working Group. Therefore, cFAP and aFAP have been lumped into one disease entity, classic or attenuated familial adenomatous polyposis (MONDO:0021057) in this curation. Note that APC variants have been also associated with Gastric Adenocarcinoma and Proximal Polyposis of the Stomach Syndrome (GAPPS) and were curated separately. 3 frameshift variants between codons 178 and 1580 identified from 6 cFAP patients (PMID: 8162051) and 2 frameshift variants (PMIDs:8625067 and 9824584 at 5’ and 3’ ends respectively) identified from 9 aFAP patients were included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease association is also supported by experimental evidence (6 points) including two mouse models showing intestinal polyps and tumor formation for mice bearing APC truncations (PMIDs: 7753829 and 8090754) as well as functional alteration assays in patient colon cells displaying differential localization of beta-catenin in cells with mutations in APC compared to wild type (PMID: 8521819). In addition, experiments in non-patient cells show APC truncating variants affect cell cycle progression in mouse NIH 3T3 cells, and failure of truncated APC to inhibit growth of monkey kidney fibroblast CV-11 cells (PMID: 8521819). In summary, heterozygous APC truncating mutations are definitively associated (18 points) with classic or attenuated familial adenomatous polyposis (MONDO:0021057). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0017790
Submitter: ClinGen
APC variants have been associated with familial adenomatous polyposis (FAP) and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). Per criteria outlined by the ClinGen Lumping an1d Splitting Working Group, we found differences in phenotypic variability. Therefore, this curation focuses solely on autosomal dominant GAPPS. The gene-disease relationship between APC and FAP was curated separately. APC was first reported in relation to autosomal dominant GAPPS (MONDO:0017790) in family pedigrees displaying fundic gland polyps but lacking a causal gene (PMID: 21813476). Li et al summarized these families, added additional families, identified causal variants through linkage analysis of a large family with 27 affected members to a region in the APC promoter and performed experimental assays (PMID:27087319). This autosomal dominant condition causes numerous fundic gland polyps and is associated with an increased incidence of gastric cancer. At least 5 probands from families with variants segregating with disease demonstrated rare, noncoding promoter variants that alter the YY1 transcription factor binding site in the APC promoter. There are multiple additional publications, including the following PMIDs: 27343414, 29141268, 31409086, 33242120. Through cases and segregation data, the maximum score for genetic evidence has been reached (12 points). This gene-disease association is also supported by experimental evidence (3 points) including decreased transcriptional activity in luciferase reporter plasmids with the YY1 binding motif disrupted across 4 cancer cell lines, EMSA assays display binding of YY1 and DNA motifs in two cancer cell lines and quantification of YY1 binding to the wild-type APC promoter (PMID:27087319). In summary, APC promoter 1B variants in the YY1 binding motif are definitively associated with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS, MONDO:0017790). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0021056
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007608
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0017790
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0017790
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0021056
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0021056
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Dental; Dermatologic; Musculoskeletal; Oncologic; Ophthalmologic
Intervention: Oncologic
Rationale: 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
Comments: Gastric adenocarcinoma and proximal polyposis of the stomach results from variants in the APC gene promoter 1B
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to APC variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000038.6. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 10 | 6 | 21 | 2772 | 296 | 3105 |
| missense | 61 | 38 | 7707 | 351 | 34 | 8191 |
| nonsense | 567 | 93 | 14 | 674 | ||
| start loss | 3 | 2 | 5 | |||
| frameshift | 1490 | 287 | 57 | 1834 | ||
| splice donor/acceptor (+/-2bp) | 46 | 94 | 18 | 1 | 159 | |
| Total | 2177 | 518 | 7819 | 3124 | 330 | 13968 |
Highest pathogenic variant AF is 0.0012391282
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000029.2 | 15 | MANE Select | |
| Ensembl | ENSP00000257430.4 | 15 | MANE Select | |
| RefSeq | NP_001120982.1 | 15 | Standard | |
| RefSeq | NP_001120983.2 | 14 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| apc | Danio rerio | Structure: hepatocyte Quality: increased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- 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)
Biological Process
- mitotic cytokinesis
- cell fate specification
- cellular response to DNA damage stimulus
- negative regulation of microtubule depolymerization
- cell cycle arrest
Molecular Function
- protein binding
- beta-catenin binding
- microtubule binding
- protein kinase regulator activity
- protein kinase binding
Cellular Component
- kinetochore
- nucleus
- nucleoplasm
- cytoplasm
- centrosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000457016
- Coding exons
- 15
- Length
- 138742
- Individuals with no LoFs
- 125710
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 38
- Defined
- 125748
- p
- 0.000151
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.168 | 1436 | 1.45e+3 | 0.988 | 0.0000754 | 18618 |
| Missense (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 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00018 | rare |
| Latino/Admixed American | 0.00029 | 0.00029 | rare |
| Ashkenazi Jewish | 0.00011 | 0.000099 | rare |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.00028 | 0.00023 | rare |
| European (Non-Finnish) | 0.00012 | 0.00012 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- 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.;
Recessive Scores
- pRec
- 0.571
Intolerance Scores
- LoFtool
- 0.00386
- RVIS EVS
- -2.52
- RVIS percentile EVS
- 0.9
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.859
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |