Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification
Polymerase Chain Reaction/Sequencing
- Acceptable diagnostic or predictive test for FAP
- For classic FAP, consider APC sequencing and deletion/duplication testing
Polymerase Chain Reaction/Sequencing
Diagnostic or predictive test for MAP
Related Tests
Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray/Sequencing/Multiplex Ligation-dependent Probe Amplification
Recommended test to confirm a diagnosis of hereditary gastrointestinal (GI) cancer in individuals with a personal or family history of GI cancer and/or polyposis
Polymerase Chain Reaction/Sequencing
- Useful when a pathogenic familial variant identifiable by sequencing is known
- A copy of a relative’s lab report is REQUIRED
Multiplex Ligation-dependent Probe Amplification
- Use to asses for large deletion/duplication previously identified in a family member
- A copy of a relative’s lab report is REQUIRED
Familial adenomatous polyposis (FAP) is caused by pathogenic variants in the APC gene resulting in the development of hundreds to thousands of adenomatous colonic polyps beginning in early adolescence. The lifetime risk for cancer in individuals with FAP is 100 percent. Additional symptoms may include dental anomalies, polyps of the gastric fundus and duodenum, and congenital hypertrophy of the retinal pigment epithelium (CHRPE). Pathogenic APC variants may also cause other related syndromes, including attenuated FAP (AFAP), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), Gardner syndrome, and Turcot syndrome.
MUTYH-associated polyposis (MAP), caused by biallelic pathogenic variants in the MUTYH gene, can result in the development of colon polyps that are less numerous (typically 10-100) and is often diagnosed later in life. Genetic testing may be used to assess individuals at risk for FAP, other APC-associated polyposis, or MAP due to a suggestive personal or family history.
Disease Overview
Incidence/Prevalence
- Colorectal cancer (CRC): ~140,000/year in U.S.
- Lifetime risk of developing CRC: 6%
- Majority of CRC is not hereditary or inherited
- FAP and MAP each account for <1% of CRC cases
- ~1% of White individuals are predicted to carry a single pathogenic MUTYH variant
Age of Onset
- FAP: early adolescence
- MAP: third decade of life or later
Symptoms
FAP
- Development of hundreds to thousands of adenomatous colonic polyps
- Dental anomalies
- Polyps of gastric fundus and duodenum
- Congenital hypertrophy of retinal pigment epithelium (CHRPE)
- Begins generally during early adolescence
- Overall age range of 7-36 years
- Without a preventive colectomy, all individuals with FAP will develop colon cancer during their lifetime
- Mean age at time of diagnosis is 39 years
AFAP
Differs from FAP:
- Typically fewer polyps; 10-100, with an average of 30
- More proximally located polyps
- Cancer generally occurs at a later age
Gardner Syndrome
- Occurs in 20% of families with classic FAP
- Associated with:
- Benign osteomas
- Desmoid tumors
- Soft-tissue tumors
Turcot Syndrome
- Colon polyps
- Central nervous system tumors
- Associated with medulloblastoma
- Often caused by pathogenic variants in APC gene
- Turcot with glioblastoma multiforme is usually caused by pathogenic variants in a mismatch repair gene
GAPPS
- Associated with pathogenic variants in promoter 1B of the APC gene
- Fundic gland polyposis
- Increased risk for gastric cancer
MAP
- 10-100 polyps
- ~20-30% of patients with 10-100 polyps have biallelic pathogenic MUTYH variants
- Age of onset is third decade or later
Genetics
Genes
APC, MUTYH
Inheritance
- APC is autosomal dominant
- MUTYH is autosomal recessive
Penetrance
- Classic FAP: 100% in untreated individuals
- Individuals with MAP and colorectal cancer
De novo Variants
APC: 25% of cases
Test Interpretation
Sensitivity/Specificity
Analytical sensitivity/specificity: 99% for APC and MUTYH
Clinical Sensitivity
Results
Positive
- Identification of a single pathogenic variant in APC gene
- Predictive of FAP or APC-associated polyposis
- Detection of two pathogenic MUTYH variants on opposite chromosomes
- Predictive of MAP
- Identification of a single pathogenic MUTYH variant
- Individual is a carrier of MAP
- Individual could be affected if another unidentified pathogenic MUTYH variant is present on the opposite chromosome
- Possible increased risk for cancer has been associated but is not well defined
Negative
- No pathogenic variants were detected in APC or MUTYH genes
- Does not rule out FAP, APC-associated polyposis, or MAP
Inconclusive
- Variant(s) of unknown clinical significance may be detected
Limitations
Diagnostic errors can occur due to rare sequence variations
APC Gene
- Deep intronic or regulatory region variants will not be identified
- Breakpoints of large deletions/duplications will not be determined
MUTYH Gene
- FAP panel: only two pathogenic MUTYH variants will be tested (Y165C and G382D)
- Not detected on the MUTYH Sequencing test:
- Large deletions or duplications
- Deep intronic, regulatory region, or promoter pathogenic variants
References
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Lagarde A, Rouleau E, Ferrari A, et al. Germline APC mutation spectrum derived from 863 genomic variations identified through a 15-year medical genetics service to French patients with FAP. J Med Genet. 2010;47(10):721-722.
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Aretz S, Stienen D, Uhlhaas S, et al. Large submicroscopic genomic APC deletions are a common cause of typical familial adenomatous polyposis. J Med Genet. 2005;42(2):185-192.
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Aretz S, Genuardi M, Hes FJ. Clinical utility gene card for: MUTYH-associated polyposis (MAP), autosomal recessive colorectal adenomatous polyposis, multiple colorectal adenomas, multiple adenomatous polyps (MAP) - update 2012. Eur J Hum Genet. 2013;21(1).
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Inra JA, Steyerberg EW, Grover S, et al. Racial variation in frequency and phenotypes of APC and MUTYH mutations in 6,169 individuals undergoing genetic testing. Genet Med. 2015;17(10):815-821.
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Out AA, Tops CM, Nielsen M, et al. Leiden open variation database of the MUTYH gene. Hum Mutat. 2010;31(11):1205-1215.
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Nielsen M, Infante E, Brand R. MUTYH polyposis. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews: University of Washington; 1993-2020. [Last Update: Oct 2019; Accessed: Feb 2020]
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Li J, Woods SL, Healey S, et al. Point mutations in exon 1B of APC reveal gastric adenocarcinoma and proximal polyposis of the stomach as a familial adenomatous polyposis variant. Am J Hum Genet. 2016;98(5):830-842.
NCCN - Genetic/Familial High-Risk Assessment: Colorectal v1.2018
NCCN clinical practice guidelines in oncology, genetic/familial high-risk assessment: colorectal, Version 1.2018. National Comprehensive Cancer Network. [Updated: Jul 2018; Accessed: Jan 2019]
Preferred diagnostic or predictive test for FAP and MAP