Familial adenomatous polyposis (FAP)

Familial adenomatous polyposis is a colorectal cancer predisposition syndrome characterized by hundreds to thousands of adenomatous polyps in the gastrointestinal tract. 

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Test Code: 3040 Test Name: APC seq and del/dup TAT 14-21 days Gene: 1
Test Code: 3042 Test Name: APC specific site analysis TAT 7-14 days Gene: 1
Test Code: 8726 Test Name: APC & MUTYH seq and del/dup TAT 14-21 days Genes: 2

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Why Is This Important?

  1. Option to modify frequency and initial age of colonoscopy and other screening
  2. Consideration of prophylactic colectomy or other risk-reducing measures, as appropriate
  3. Identify at-risk family members

When To Consider Testing

Based on published guidelines1APC genetic testing should be considered for any of the following:

  • A personal history of ?10 adenomas
  • A personal history of adenomas and any of the following manifestations: duodenal/ampullary adenomas, desmoid tumors, papillary thyroid
    cancer, CHRPE, epidermal cysts, and/or osteomas
  • Family history of FAP
  • A known APC mutation in the family

Mutation Detection Rate

Prevalence of APC mutations among those with polyposis depends on the phenotype.2 

Detection rates are highest in those with classic FAP and those with a family history of polyposis (clinical sensitivity). Ambry's APC analysis can detect >99.9% of described mutations in the gene, when present (analytic sensitivity).

Test Description

APC coding exons 1-15 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for coding exons 1-15. Additionally, all promoter 1B gross deletions as well as single nucleotide substitutions within the promoter 1B YY1 binding motif are analyzed and reported. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology, using long biotinylated oligonucleotide probes followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing. Gross deletion/duplication analysis of APC using read-depth from NGS data is also performed. Any copy number changes detected by NGS are confirmed by targeted chromosomal microarray and/or multiplex ligation-dependent probe amplification (MLPA).

 

1. Syngal S, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015. 110(2):223-62.

2. Grover S, et al. Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas. JAMA. 2012. 308(5):485-492.

3. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.

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