APC Gene Curation
- Andrea Oza
Gene-disease assertions not curated here (add link or write note):
Disease | Familial adenomatous polyposis |
|---|---|
Inheritance | Autosomal dominant |
Prevalence | 1-9 / 100 000 (rare) Orphanet:733 |
Rapid or full curation? | Rapid Full |
ClinGen Hereditary Cancer GCEP - classification from 6/20/2022, accessed 06/22/2023 | |
Clinical Validity Scoring Notes and points | 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. ClinGen Hereditary Cancer GCEP - classification from 6/20/2022, accessed 06/22/2023 |
Clinical Validity Points Total | 18 |
Clinical Validity Classification Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed | Definitive |
Molecular Mechanism Loss of function Gain of function Dominant negative Unknown Other | Loss of function (per summary from ClinGen Hereditary Cancer GCEP)
|
Penetrance Complete (100%) High (≥90%) Reduced (<90% and >10%) Low (≤10%) (list source/PMID) | Reduced (age-related) Source: PMID: 20301519 |
Age of Onset Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID) | Childhood to adulthood Source: PMID: 20301519 |
Severity | Moderate |
Clinical Features | Predisposition to colorectal cancer. Classic FAP is characterized by hundreds to thousands of adenomatous colonic polyps, beginning on average at age 16 years (range 7-36). Attenuated FAP is characterized by multiple colonic polyps, more proximally located polyps, and a later diagnosis than classic FAP. Extracolonic manifestations may include polyps of the stomach and duodenum, osteomas, dental abnormalities (supernumerary teeth, unerupted teeth, congenital absence of 1 or more teeth, odontomas), congenital hypertrophy of the retinal pigment epithelium (CHRPE), benign cutaneous lesions (epidermoid cysts, fibromas, pilomatricomas), desmoid tumors, adrenal masses, papillary thyroid carcinoma, medulloblastoma, hepatoblastoma, Source: PMID: 20301519 |
HPO terms | HP:0003003 Colon cancer |
Gene SOPs & Notes | The InSiGHT VCEP has specified the ACMG/AMP guidelines for APC interpretation. Important items are highlighted below. PVS1 - There are specific guidelines to follow for applying PVS1. Follow the InSiGHT VCEP guidelines. PM2 ≤ 0.0003% PS4 - Follow specific phenotype points scoring from Table 1
Transcripts: Preferred transcript for coding, intronic and promoter 1A variants is NM_000038.6. For the promoter 1B deletion the preferred transcript is NM_001127511.3, which has an alternative coding exon 1 |
Curation Summary: | The APC gene is associated with autosomal dominant familial adenomatous polyposis FAP, which can present in a classic or attenuated form. Classic FAP is characterized by hundreds to thousands of adenomatous colonic polyps, and attenuated FAP is characterized by multiple colonic polyps and a later age of diagnosis. Other manifestations of FAP include polyps of the stomach and duodenum, osteomas, dental abnormalities (supernumerary teeth, unerupted teeth, congenital absence of 1 or more teeth, odontomas), congenital hypertrophy of the retinal pigment epithelium (CHRPE), benign cutaneous lesions (epidermoid cysts, fibromas, pilomatricomas), desmoid tumors, adrenal masses, papillary thyroid carcinoma, medulloblastoma, and hepatoblastoma. The APC gene is also associated with autosomal dominant gastric adenocarcinoma and polyposis of the stomach (GAPPS), which is characterized by an increased risk of gastric adenocarcinoma but no duodenal or colonic involvement in most individuals. PMID: 20301519 |
Case ID, Curator name, Date, Jira ticket link | Partially complete 06.22.2023, updated to completion 07.21.2023. Andrea Oza https://broadinstitute.atlassian.net/browse/CIT-130 |
Disease | Gastric adenocarcinoma and polyposis of the stomach |
|---|---|
Inheritance | Autosomal dominant |
Prevalence | <1/1 000000 ORPHA:314022 |
Rapid or full curation? | Rapid Full |
ClinGen Hereditary Cancer GCEP, accessed 07.21.2023 | |
Clinical Validity Scoring Notes and points | 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. ClinGen Hereditary Cancer GCEP, accessed 07.21.2023 |
Clinical Validity Points Total | 13 |
Clinical Validity Classification | Definitive ClinGen Hereditary Cancer GCEP, accessed 07.21.2023 |
Molecular Mechanism | Likely loss of function, decreased expression due to variants in promoter 1B 6 variants in HGMD associated with Gastric adenocarcinoma and proximal polyposis of the stomach, all are in the 5' UTR or upstream of APC located in promoter 1B. All first reported in PMID: 27087319. Functional studies were also performed. Luciferase assays indicated reduced binding of a transcription factor and impaired activity of the APC promoter. Analysis of blood and saliva from affected individuals showed allelic imbalance, indicating these variants led to decreased expression. |
Penetrance (list source/PMID) | Unknown |
Age of Onset (list source/PMID) | Pediatric to adulthood PMID: 27087319 |
Severity | Moderate |
Clinical Features | Proximal gastric polyposis, increased risk of gastric adenocarcinoma, no duodenal or colonic involvement in most individuals. PMID: 20301519 |
HPO terms | HP:0033770 Gastric adenocarcinoma |
Gene SOPs & Notes | All variants are located in promoter 1B. |
Curation Summary: | see above |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza 07.21.2023 https://broadinstitute.atlassian.net/browse/BCL-1 |