MUTYH-associated polyposis (MAP)

MUTYH-associated polyposis is a colorectal cancer predisposition syndrome typically characterized by tens to hundreds of adenomatous polyps in the gastrointestinal tract.

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Test Code: 4661 Test Name: MUTYH seq and del/dup TAT 14-21 days Gene: 1
Test Code: 4662 Test Name: MUTYH 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

MUTYH testing may be considered in patients with a personal or family history of any of the following:1-3

  • >10 colorectal adenomas
  • Colorectal cancer diagnosed before age 40
  • A family history of colorectal cancer consistent with autosomal recessive inheritance
  • >20 serrated polyps of any size distributed throughout the colon with some adenomas
  • Known MUTYH mutation(s) in the family

Mutation Detection Rate

MUTYH mutations are detected in 5-10% of patients with 10-999 adenomas (clinical sensitivity).1

Ambry’s MUTYH analysis is capable of detecting >99.9% of described mutations in the gene, when present (analytic sensitivity).

Test Description

MUTYH coding exons 1-16 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 1-16.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 MUTYH 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. Grover S, et al. Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas. JAMA. 2012. 308(5):485-92.

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

3. Hegde M, et al. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014. 16(1):101-16.

4. 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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