Intro to Genetics
FAP Genetics
FAP Inheritence
Genetic Testing
Forms of FAP
Impact of Genetics
What is fap?
Familial Adenomatous Polyposis (FAP)
Familial Adenomatous Polyposis (FAP) is a rare, inherited genetic disorder that causes the development of hundreds to thousands of adenoma polyps (precancerous growths) throughout the colon and rectum, typically beginning in adolescence or early adulthood. These polyps inevitably will transform into colorectal cancer if left untreated.
FAP is rare, affecting approximately 1 in 5,000 to 1 in 18,000 people. It follows an autosomal dominant inheritance pattern, meaning if you have FAP, there’s a 50% chance each of your children will inherit the condition from you. The condition is caused by germline mutations in the APC (Adenomatous Polyposis Coli) gene.
Although FAP accounts for less than 1% of all colorectal cancer cases, it is one of the most well-understood hereditary cancer syndromes, and the medical knowledge for managing it has advanced dramatically. Without treatment, nearly 100% of people with FAP will develop colorectal cancer, typically by age 40—but with proper surveillance and modern treatment, this outcome is preventable.
Why Advocacy Is Needed
While FAP is rare, those living with it face unique and significant challenges. Many healthcare providers are unfamiliar with FAP including protocols for diagnosis and surveillances which can lead to delayed diagnosis or inappropriate care. Patients must make major life decisions about surgery at a young age, manage frequent medical surveillance, and live with ongoing cancer anxiety. FAP affects not just the colon but multiple organ systems including but not limited to the stomach, duodenum, thyroid, liver, duct systems, and central nervous system yet surveillance guidelines for these areas remain inconsistent across institutions. The lifetime of medical monitoring and potential surgeries that is required to best manage FAP can have profound psychological and lifestyle impacts.
While surgery remains the definitive treatment, patients and families face significant challenges in accessing specialized FAP care and coordinated surveillance. Families navigate emotional complexity around genetic counseling and the difficult decision to test children and relatives who may carry the mutation. Many patients encounter substantial financial burdens related to lifelong surveillance, frequent specialist visits, and major surgical interventions. The absence of medical alternatives to prevent polyp development means early detection through screening and timely surgical management are critical, yet not all regions have access to experienced FAP centers or multidisciplinary teams equipped to manage this complex condition.
Life’s a Polyp Foundation advocates for improved FAP screening and surveillance guidelines, increased research funding for new therapies, enhanced genetic counseling resources for patients and families, comprehensive support services, and equitable access to innovative treatments.
Intro to Genetics
What is Genetics?
Genetics is the study of how the little segments of our DNA, called genes, behave and interact with other molecules under varying conditions. Genetics is what tells us how a mutation is inherited within a family. It also helps us understand how a given mutation impacts the protein that the gene will ultimately encode.
Before we get too far into the genetics of FAP, this section will help orient you to the terminology and basic principles so you feel comfortable as you begin to learn.
What Are Genes?
Genes exist on chromosomes and are made up of DNA. There are many genes on each chromosome. A gene’s structure involves exons that are coding regions for making a protein. Within an exon are little sequences called codons. A codon codes, or makes, a single amino acid. These amino acids are then strung together to make a protein. These proteins then do the majority of work in cells, creating structure, function, and regulation of the body. Not all genes code for proteins; some work to help control other genes.
The APC gene has approximately 15 coding exons and direct sequencing, or testing, of all 15 coding exons is considered the gold standard for detecting mutations.
The Terminology
When discussing FAP and genetic changes, it is common to see 5′ and 3′. These are short for 5-prime and 3-prime and refer to the 5th and 3rd carbon atoms at the ends in the sugar molecule of DNA/RNA. Knowing this simply helps in understanding what the terms mean in relation to where the identified mutation is located.
Mutations located between codons 1000-4000 are associated with classic FAP and mutations found in the peripheral 5′ and 3′ regions are associated with AFAP.
Mutational hotspots for FAP are located in the 5′ part of exon 15 at codons 1309-1061 of the APC gene. Due to the number of mutations from codons 1250-1464, this area is termed the mutation cluster region.
Extracolonic manifestations tend to be located in mutations beyond codon 1400.
What Do Mutations Do?
Some mutations increase the likelihood of desmoid tumors (benign but potentially aggressive abdominal growths occurring in 10-25% of FAP patients), while others increase thyroid cancer risk. Women with FAP have about a 2% risk of thyroid cancer, particularly those from Latinx populations who may have higher risk. Thyroid screening typically starts in the teenage years for those with FAP.
For example, mutations between codons 311 and 411 and in the 3′ region are associated with CHRPE.
Mutations after codon 1400 are associated with osteomas and desmoid tumors while thyroid tumors are related to mutations between codons 140-1309. Gastric and duodenal polyps are related to mutations at the 3′ end before codon 1395, exon 4 and codons 564-1493.
A small number of FAP patients (less than 1%) may develop hepatoblastoma, a type of liver cancer in young children occurring primarily before the age of 3 but monitoring is recommended through age 5 —another reason pediatric screening is important for children diagnosed with FAP. The majority of mutations for hepatoblastoma are located on the 5′ to mid region of the APC gene between codons 141-1751.
Your genetic counselor and medical provider can discuss what your specific mutation means for your personal health trajectory and surveillance needs
The primary treatment for FAP remains surveillance and surgery to prevent cancers. Studies have shown chemoprevention medications and supplements to aid in polyp management with FAP that can be helpful in delaying surgery.
Sources: https://medlineplus.gov/genetics/understanding/ | https://pmc.ncbi.nlm.nih.gov/articles/PMC4404874 | https://www.ncbi.nlm.nih.gov/books/NBK21134/ | https://jgld.ro/jgld/index.php/jgld/article/view/961 | https://pmc.ncbi.nlm.nih.gov/articles/PMC4404874 | https://jgld.ro/jgld/index.php/jgld/article/view/961 | https://pmc.ncbi.nlm.nih.gov/articles/PMC4404874/ | https://www.ncbi.nlm.nih.gov/books/NBK1345/ | https://pmc.ncbi.nlm.nih.gov/articles/PMC4404874/
Understanding the Genetics of FAP
How the APC Gene Works
Think of your genes as instruction manuals that tell your body how to build and maintain healthy cells. Each person has two copies of most genes—one inherited from each parent. FAP develops when someone inherits a defective copy of a specific gene called APC (Adenomatous Polyposis Coli).
The healthy APC gene acts like a “quality control manager” for cells in your body. It tells cells when to stop dividing, ensures they’re arranged properly, and removes cells that become abnormal. When this gene is working correctly, it prevents uncontrolled cell growth and polyp formation. It does this by inhibiting, or negatively regulating, the β-catenin oncoprotein.
How FAP Develops: The “Two-Hit” Scenario
Everyone inherits one copy of the APC gene from each parent. In families with FAP, someone inherits a defective copy from an affected parent. This means approximately 70-80% of people with FAP inherited the mutation from a parent; the remaining 20-30% developed a new mutation by chance – a de novo mutation that was not present in either parent.
In a germline APC mutation, the mutation is present in every cell of the body. Individuals with FAP are born with the first step toward adenoma polyp formation already in place. However, most adenomas do not develop until a second genetic event occurs within an individual cell.
FAP is considered a classic example of Knudson’s two-hit hypothesis, which describes how many hereditary cancer syndromes develop.
The APC mutation represents the first hit. A second event, often referred to as the second hit, occurs when the remaining functional APC gene copy becomes inactivated within a specific cell. This can occur through several molecular mechanisms including:
- Loss of heterozygosity (LOH), where the normal APC allele is lost or replaced
- Truncating mutations, such as nonsense or frameshift variants, that prevent production of a functional protein
- Other genetic alterations that disrupt normal APC function
Once both APC gene copies are no longer functioning correctly, the affected cell loses an important mechanism for controlling growth and regulating the Wnt/β-catenin signaling pathway. The cell can then begin to proliferate abnormally, leading to the formation of an adenoma polyp.
Because the colon contains billions of epithelial cells that continually divide throughout life, these second-hit events occur independently in many different cells. Over time, this results in the development of hundres to thousands of adenomatous polyps, which is the hallmark of FAP. This is why surgery becomes necessary—the problem is so widespread that medications and colonoscopies alone cannot manage it long-term.
Understanding the type of mutation a person has is important for better understanding the individual differences in disease manifestation that person may experience as well as for treatment planning. The type of APC mutation will determine the nature of that second hit. When the mutation occurs between codons 1194-1392, it is strongly associated with an allelic loss of APC as the second hit, meaning the gene has lost one of its inherited gene copies and loses its normal control mechanism and instead promotes tumor development. If the mutation occurs outside of the 1194-1392 codon region, it is most likely that the second hit is from a truncating mutation in the mutation cluster region between codons 1250-1464. This means it’s a nonsense mutation that’s led to a premature stop to coding sequence for the protein, resulting in the protein being non-functional in most cases.
Source: https://pmc.ncbi.nlm.nih.gov/articles/PMC4404874/ | https://www.foxchase.org/about-us/history/discoveries-fox-chase-research/knudsons-two-hit-theory-cancer-causation | https://pmc.ncbi.nlm.nih.gov/articles/PMC8694077/ | https://pmc.ncbi.nlm.nih.gov/articles/PMC11444336/ | https://pmc.ncbi.nlm.nih.gov/articles/PMC11444336/
Most APC gene mutations are nonsense mutations that lead to a truncated protein. These primarily occur in the 5′ half of the APC gene resulting in the elimination of most, or all, of the 20-aminoacid repeats that are involved in regulating β-catenin levels.
Types of APC Mutations
Missense mutations
a codon is altered, resulting in a different amino acid in the protein
Splicing mutations
alter regulatory sequences at splice sites, interrupting normal sequence
Deletions and duplications
remove or duplicate genetic information; can be gross or small changes
De Novo
spontaneous mutation with no family history of FAP
Germline mosaicism
APC mutations affecting only a subset of cells in specific organs rather than every cell
Important Note: Many individuals with FAP have no symptoms and are only identified through genetic testing of at-risk relatives. In 2024, it was estimated that 20-30% of FAP patients lack a documented family history of FAP. This is why family screening is crucial.
How FAP Runs in Families
Inheritance
FAP is a germline mutation and follows an autosomal dominant inheritance pattern. This scientific terminology simply means: the mutation is in the reproductive cells (sperm or egg) and if you have the faulty gene, there’s a 50% chance each of your children will inherit it from you, and a 50% chance they won’t. It doesn’t mean every other child will be affected—each child has an independent 50/50 chance, like flipping a coin. The gene can be passed from either affected parent, and it affects males and females equally.
Jenny’s grandpa and his sister. Both inherited FAP.
Jenny’s great-grandmother, who inherited FAP from one of her parents.
Genetic Testing
What About Genetic Testing?
Genetic testing examines your DNA to identify whether you carry a known APC mutation. If you have FAP or come from a family with FAP, genetic testing can tell you whether you inherited the mutation. A positive result confirms FAP and guides your medical team in planning surveillance and treatment. A negative result in someone with a family history means you didn’t inherit any known mutation. Based on individual factors your doctor may still recommend periodic screening.
Scientists continue to discover new mutations for FAP on the APC gene. Due to this, FAP can be diagnosed by phenotype when criteria are met in light of a negative genetic result.
Alternatively, some individuals are diagnosed with Colonic Adenomatous Polyposis of Unknown Etiology burden and are recommended to receive the surveillance and treatment based on adenoma burden per NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).
There is also the possibility for genes to not have mutations but present phenotypically of a disease. This can occur due to epigenetic mechanisms that affect how genes are expressed without changing the underlying genetic code.
One important epigenetic mechanism is DNA methylation that turns on or off a gene. Methylation occurs when the methyl (CH3) group is added to DNA, this modifies the gene’s function by how the gene is expressed. With increased methylation, a gene can be turned off or silenced whereas decreased methylation (demethylation) can turn on a gene.
Epigenetic alterations can contribute to disease development affecting the expression of genes involved in cell growth, DNA repair, and tumor suppression. In some cases, abnormal methylation patterns can mimic the effects of genetic mutations by reducing the activity of otherwise normal genes.
This means, genetic diseases can occur without any genetic mutations. In such cases, an Immunohistochemistry (IHC) test can confirm if this is occurring in tumors for some diseases such as Lynch Syndrome. However, IHC is not a standard diagnostic test for FAP.
While APC mutations remain the primary cause of FAP, understanding both genetic and epigenetic mechanisms provides a more complete picture of how polyps in FAP develop and progress.
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Forms of FAP
Clinical Variants and Genetic Spectrum of FAP
FAP doesn’t look identical in every patient—the severity and type of manifestations depend on where exactly on the APC gene the mutation occurs. Your specific genetic variant helps your medical team predict how aggressively your FAP will progress and what additional health complications you might need to monitor.
Classic FAP is the most common form, characterized by the development of 100 or more polyps throughout the colon beginning in the late teens or early twenties. Polyps accumulate rapidly, and without surgery, nearly all individuals develop colorectal cancer by their 40s or 50s.
Attenuated FAP (AFAP) is a often described as a milder variant where patients develop 20 to 99 polyps instead. These polyps tend to appear later in life (typically in the 40s or 50s) and progress more slowly. The cancer risk is still significant—about 70% over a lifetime—but it develops later than in classic FAP. This means surveillance might start slightly later and people may have more time before requiring surgery. AFAP patients remain at risk for the same extra-colonic manifestations and associated cancers of FAP in spite of the later age onset of polyp development and decreased polyp burden. In rare cases, some individuals develop severe polyposis with over 1,000 polyps, requiring urgent surgical intervention.
Jenny’s great aunt as an adult, who inherited FAP.
Mosaic FAP is a term that is appearing more among FAP online communities but actually isn’t new, it was first discovered in FAP patients in 1999. This is a de novo mutation where the APC mutation has been found to only affect a subset of cells in specific singular or multiple tissues or organs rather than in every cell of the body. The cells affected depend on when the mutation occurred during embryogenesis (the process of a fertilized egg dividing and developing into an embryo).
Standard testing for Mosaic FAP involves leukocyte DNA – testing the DNA of white blood cells. However, mosaicism is not always identified through this method and instead, DNA sequencing is an alternative. Because mosaicism is not a germline mutation, a blood or saliva test is not adequate. Instead, testing of identified tissues suspected to have the FAP mutation must be tested – such as a polyp or desmoid.
Testing type matters as 4-11% of patients with abnormally high number of colorectal polyps but no known cause for the polyposis condition were identified to have Mosaic FAP through leukocyte DNA testing yet studies that completed DNA sequencing on colorectal polyps, 25-50% of the patients were found to have Mosaic FAP. This leads further credence for the need for continued research for FAP, especially when patients may not meet the standard for testing of polyposis conditions but may still have a mosaicism mutation occurring.
Sources: https://pmc.ncbi.nlm.nih.gov/articles/PMC4404874/ | https://sciencedirect.com/science/article/pii/S0016508525062109 | https://pmc.ncbi.nlm.nih.gov/articles/PMC7725418
Gardner’s Syndrome: FAP is sometimes referred to as Gardner’s Syndrome. This was described as a variation early on, prior to the level of understanding about FAP that is now known. However, some publications continue to refer to Gardner’s as a subtype of FAP. However, the National Comprehensive Cancer Network® (NCCN®) does not recognize this as a FAP variant per NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, 2025.
Turcot Syndrome: If a brain tumor occurs in someone with either FAP or a hereditary non-polyposis colorectal cancer condition, it has been referred to previously as Turcot Syndrome. However, the NCCN does not recognize this as a FAP variant per NCCN Guidelines.
OMIM, provides an interesting history of genetic discoveries along the way of FAP, primarily from the 1950’s to 2000’s, although some as recent as 2016.
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric V.1.2025.
© 2025 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed January 8, 2026.
To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
Genotype–Phenotype Correlations in FAP
How Gene Location Affects Health Risks
Beyond polyp burden, the location of your APC mutation influences your risk for other health problems associated with FAP. While the language of mutation locations on the APC gene is quite technical and can be difficult to understand, it is vital information for your medical provider to anticipate possible FAP manifestations for surveillance and treatment planning.
The APC gene is a tumor suppressor gene and is located on the region of chromosome 5, band q21-22. It provides instructions by encoding a 312-kDa protein – the APC protein, which acts as a tumor suppressor regulating cells behavior. This is primarily done by controlling the Wnt signaling pathway and beta-catenin levels. Beta-catenin is a protein that primarily holds cells together and serves as a messenger to controlling gene activity through the Wnt pathway by telling genes when to turn on for cell growth, division, and differentiation.
CHRPE
mutations between codons 311-411 and in the 3′ region
Desmoid tumors and osteomas
mutations after codon 1400
Thyroid tumors
mutations between codons 140-1309
Gastric and duodenal polyps
mutations at the 3′ end before codon 1395, exon 4, and codons 564-1493
Hepatoblastoma
majority of mutations in the 5′ to mid region between codons 141-1751
Extracolonic manifestations
Extracolonic manifestations generally occur in mutations beyond codon 1400
Your genetic counselor and medical provider can discuss what your specific mutation means for your personal health trajectory and surveillance needs.
Education Resources
Empower Yourself – Learn from These Expert Resources
FAP & Me – A Guide to Familial Adenomatous Polyposis
A note to Parents
Welcome to “FAP & Me!” This booklet was written to reinforce the information about FAP that you, your doctors, and your genetic counselor have given your child. FAP & Me is useful in various ways, depending on the age of the child. Each child and family is different, and FAP & Me may have information that you have not shared with your child yet.
Please review FAP & Me to see whether the information is right for your child at this time. Your child may like reading FAP & Me with you, an older sibling, or another adult so that he or she can ask questions and have you explain things. We hope that FAP & Me is helpful!
– FAP & Me, a publication of the National Society of Genetic Counselors
A Patient’s Guide to FAP
The content in this guide is based on the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology “Genetic/Familial High-Risk Assessment: Colorectal” (2015).
This guide is intended to provide information for those affected by hereditary colon cancer syndromes and should not replace discussions or advice from your medical provider. We suggest you read this Guide in the order in which it is written, as each section builds upon information in previous sections. Medical terms in blue are explained in the glossary.
– paraphrased from ‘A Patient’s Guide to FAP’
Life’s a Polyp with Zeke and Katie
Yay, Yay DNA! Do You Wonder What Makes You You?
It’s all because of something called DNA.
What is DNA? It’s the instruction book for life. You have DNA. So do teeny little bugs, big elephants, tall trees, and colorful birds-every living thing has DNA! And you share DNA with just about every living thing on Earth. Join Mendel G. Cat and learn more about the tiny thin thread that connects all life.
– Mark A. Hicks
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