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Diagnosis

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Diagnosis is based primarily on clinical findings and family history. Molecular genetic testing may be used to clarify diagnosis in individuals with ambiguous findings, or for early identification of at-risk family members.

Diagnostic Testing and Evaluation

Diagnostic criteria

Familial Adenomatous Polyposis (FAP) is diagnosed in an individual with one of the following:

  • One hundred or more colorectal adenomatous polyps
  • Fewer than 100 adenomatous polyps and a relative with FAP 10 -100 adenomatous polyps and a first degree relative with FAP
  • Detection of a deleterious germline mutation in the APC gene.

First Diagnostic Steps

  • Document patient and family polyp and cancer history
  • When possible, confirm diagnoses through record review, paying particular attention to quantity and histology of polyps.
  • Consider genetic testing to confirm diagnosis, clarify diagnosis in ambiguous cases, and provide information for at-risk family members. Results could alter decisions about screening, surgical prophylaxis, and life/reproductive planning.

Testing Strategy

Testing is indicated for the following patients:

  • hepatoblastoma <age 7
  • above clinical diagnostic criteria met
  • Perform targeted genetic testing for the single specific APC gene mutation identified in a relative.
  • First-tier: sequencing and deletion/duplication analysis of the APC gene. (Detects a mutation in ~90% of individuals with classic FAP, while detection rate is lower in those with an attenuated presentation.)
  • Second-tier: testing of other genes associated with polyposis (see Differential Diagnosis)
  • When no disease-causing mutation is identified in an affected individual, but a familial cancer syndrome is still suspected, genetics consultation is appropriate.

Tests that are NOT helpful

  • Direct-to-consumer (DTC) genomic cancer screens are NOT considered an accepted testing option for Familial Adenomatous Polyposis (FAP) evaluation, because full gene analysis is not performed in those screens.

More information about DTC testing

Some direct to consumer (DTC) genomic screening companies offer risk assessment for colorectal and other cancers. Risk estimates are usually based on the detection of small, common sequence variants (single nucleotide polymorphisms or SNPs). SNPs usually have unknown function, may be outside of protein coding regions of known genes, and are associated with cancer in genome-wide association studies (GWAS). GWAS risk estimates are based on population studies, and usually provide only very small increments of absolute lifetime risk.
DTC testing panels may include a limited number of APC gene mutations, but do not rule out all known or common mutations in these genes. Therefore, DTC testing for APCmutations is not recommended when the personal or family history is suggestive of FAP.

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  • Protein truncation testing (PTT) has been replaced by more sensitive gene sequencing techniques.

Subsequent Diagnostic Evaluation

Variants
Additional diagnostic evaluation may be warranted for individuals or families with extra-colonic findings:

  • Gardner syndrome is defined as colonic polyposis plus extracolonic features (see clinical feature).
  • Turcot syndrome is a very rare subtype of Familial Adenomatous Polyposis (FAP) that involves brain tumors (specifically medulloblastomas).

Interpretation of Genetic Test Results

  • Interpretation of results depends upon the patient's polyp/cancer history, family history, and whether a familial mutation has previously been identified. Possible outcomes include:

Test Result

Interpretation

Positive

Disease-causing mutation was detected.

True Negative

The previously identified familial mutation not detected.

Uninformative Negative

No mutation was detected, but a hereditary cancer predisposition cannot be ruled out.

Variant of Uncertain Significance (VUS)

A variant of unknown functional consequence was detected. Cannot confirm or rule out an association with cancer risk.

  • For patients with true negative test results, screening recommendations for the general population apply.
  • For patients with uninformative negative or VUS results, cancer surveillance recommendations should be based on personal and family history.

More information about uninformative results.

An uninformative test result is more common than one would think. Interpretation of APCgene tests can be complicated by the fact that:
  • Several cancer predisposition syndromes have overlapping phenotypes
  • Other undiscovered genes are possible
  • Within known genes, one of several different mutations may be present
  • Some mutations have unknown functional consequences
  • Mutation detection rates for individual test panels are not 100%

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Lifestyle/Environmental Contributors to Disease

None

Differential Diagnosis

  • MUTYH-associated polyposis (MAP): Similar to attenuated Familial Adenomatous Polyposis (FAP) but due to bi-allelic mutations of the MYH gene (inherited in an autosomal recessive pattern).
  • Chromosome 5q microdeletion: Adenomatous polyposis accompanied by developmental delay; this chromosome region contains the APC gene.
  • Lynch syndrome (Hereditary non-polyposis colon cancer; HNPCC): Involves increased risk for colorectal, endometrial and other cancers associated with microsatellite instability (MSI), but few adenomatous polyps. Associated with mutations in one of four mismatch repair genes (MLH1, MSH2, MSH6, PMS2) or EPCAM.
  • Other inherited polyposis syndromes: Including Peutz-Jeghers syndrome and Juvenile Polyposis syndrome
  • Other non-inherited polyposis syndromes: Sessile Serrated Polyposis (formerly known as Hyperplastic Polyposis syndrome)
  • Sporadic colorectal and other cancers

Consensus Statements and Guidelines

Vasen HF, Möslein G, et al. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut. 2008 May;57(5):704-13.

Rex DK, DA Johnson et al. ACG Guidelines for Colorectal Cancer Screening. Am Fam Physician. 2009 Sep 15;80(6):647-651.

American Gastroenterological Association. Medical position statement: hereditary colorectal cancer and genetic testing. 2001.

American College of Medical Genetics and American Society of Human Genetics Joint Test and Technology Transfer Committee Working Group. Genetic Testing for colon cancer: Joint statement of the ACMG and ASHG. 2000.