Welcome to the Gene Scene! Each week, we will explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early. Here, we focus on the condition that led to the gene’s inclusion on the list, providing clear, relevant information that supports your clinic. To subscribe to the Gene Scene, contact your local GSL or send a request to info@ambrygen.com. 

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Clinical Phenotype Summary:  

The APC gene (NM_000038.5) is located on chromosome 5q22.2, encodes the adenomatous polyposis coli protein, and contains 15 coding exons. Pathogenic variants in this gene are known to cause APC-related familial adenomatous polyposis (FAP), APC-related attenuated familial adenomatous polyposis (AFAP), and APC-related gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), which are inherited in an autosomal dominant fashion. Loss of function has been reported as the mechanism of disease for FAP and AFAP.   

APC-related FAP and AFAP are characterized by: 
•    Significantly increased risk for multiple colorectal adenomatous polyps 
•    Colorectal cancer (cumulative lifetime risk of up to 70% for AFAP and up to 100% for FAP) 
•    Small bowel cancer 
•    Potential extracolonic manifestations such as: 
     o    Duodenal and/or gastric polyps 
     o    Desmoid tumors 
     o    Osteomas 
     o    Congenital hypertrophy of the retinal pigment epithelium (CHRPE)  
Additional cancer risks may include: 
•    Cancers of the thyroid, stomach, liver, and central nervous system 
•    Current evidence suggests these lifetime risks are between 1% and 2% 
APC-related GAPPS is characterized by: 
•    Profuse gastric polyposis  
•    Increased risk for gastric cancer 
•    Limited to no colorectal or duodenal involvement  
Current data is insufficient to determine penetrance associated with the GAPPS phenotype.  
 
Unique Considerations:  
The APC variant c.3920T>A (p.I1307K), present in 6-10% of the Ashkenazi Jewish population, is the only reported variant known to confer a moderately increased risk for colorectal cancer in the absence of polyposis. 

Rare pathogenic point mutations in the YY1 binding domain of promoter 1B region of APC are the only reported pathogenic variants in patients with GAPPS. 
 
Clinical Resources:  
Clinician Management Resource for APC and Understanding Your Positive APC Genetic Test Result 
Clinician Management Resource for APC p.I1307K and Understanding Your Moderate Risk APC Genetic Test Result 
  
Ambry Knows Genes:  
Peer-Reviewed Publications: 
•    Large-scale application of ClinGen-InSiGHT APC-specific ACMG/AMP variant classification criteria leads to substantial reduction in VUS (Sept 2024) 
Scientific Presentations:  
•    A deep dive into APC introns: Paired DNA/RNA testing identifies novel FAP and AFAP alleles in the deep intronic regions of APC (CGA-IGC 2022) 
Scientific Posters: 
•    RNA analysis and long read sequencing identify causative APC complex rearrangement in unsolved FAP case (ACMG 2025) 
•    Don’t MISS the mark: Rare missense variants in APC associated with polyposis phenotypes (CGA-ICG 2024) 
EducateNext Webinars:  
•    Solving Missing Heritability in Familial Adenomatous Polyposis Patients Using Paired DNA-RNA Testing (May 2024) 
Blog Posts: 
•    Polyposis Explained: Solving the Mystery with RNA Testing (Oct 2024) 
•    APC: New Takes on an Old Gene (March 2024) 
 
Citations:  
•    Jasperson KW. Cancer J. 2012 Jul;18(4):328-33. PMID: 22846733. 
•    Burt RW et al. Gastroenterology. 2004 Aug;127(2):444-51. PMID: 15300576. 
•    Soravia C et al. Am J Pathol. 1999 Jan; 154(1): 127–135. PMID: 9916927.  
•    Giardello F et al. Gut. 1993 Oct; 34(10): 1394–1396. PMID: 8244108. 
•    Aretz S et al. Pediatr Blood Cancer. 2006 Nov;47(6):811-8. PMID: 16317745.  
•    Liang J et al. Am. J. Epidemiol. 2013 Jun;177:1169-79. PMID: 23576677. 
•    Chenbhanich J et al. Fam Cancer. 2019 Jan;18(1):53-62). PMID: 29663106. 
•    Valle L, et al. (2023) J Med Genet 60(11):1035-1043). PMID: 37076288. 
•    Skat-Rørdam PA, et al. (2024) Hered Cancer Clin Pract 22(1):12. PMID: 39039610. 
•    Li J et al. Am. J. Hum. Genet. 2016 May;98(5):830-42. PMID: 27087319. 
•    Foretova L et al. Klin Onkol. Summer 2019;32(Supplementum2):109-117). PMID: 31409086. 

Ambry Genetics Gene-Disease Validity Scheme 

Each week, we explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early.  

To learn more about the ACMG Secondary Findings list, click here.  

To read all previous Gene Scene emails, click here.