APC- and MUTYH-Associated Polyposis Panel, Sequencing and Deletion/Duplication

To compare directly to other hereditary cancer panels offered by ARUP Laboratories, see the Hereditary Cancer Panel Comparison table.

Preferred diagnostic or predictive test for APC-associated polyposis conditions (FAP, AFAP, GAPPS, and MAP).

  • Testing for a known familial sequence variant by sequencing gene of interest. A copy of the family member’s test result documenting the familial gene variant is REQUIRED.
  • To determine if the variant(s) of interest are detectable by this assay, contact an ARUP genetic counselor at 800-242-2787.
Related Tests

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

Familial adenomatous polyposis (FAP) is an APC-associated polyposis condition 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 colorectal cancer (CRC) in individuals with FAP is 100%. 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 polyposis conditions, including attenuated FAP (AFAP) or gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS).

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 10-100s) and is often diagnosed later in life. Genetic testing may be used to assess individuals at risk for FAP, other APC-associated polyposis conditions, or MAP due to a suggestive personal or family history.

Disease Overview

Associated Disorders

Disorder Polyp and Cancer Characteristics Age of Onset Other Symptoms

FAP

Hundreds to thousands of adenomatous colonic polyps may develop

Polyps may develop in gastric fundus and duodenum

Symptom onset at 7-36 years (generally early adolescence)

Mean age of CRC diagnosis is 39 years in untreated individuals

Without preventive colectomy, all individuals will develop CRC

Dental anomalies

CHRPE

Osteomas, soft tissue tumors, desmoid tumors

AFAP

Fewer colonic polyps than FAP (10-100s, with an average of 30)

More proximally located polyps

Cancer occurs later than in FAP

Extracolonic manifestations are variable

GAPPS (associated with pathogenic variants in promoter 1B of the APC gene)

Gastric fundic gland polyposis and increased risk for gastric cancer

Limited colonic involvement

Unknown

Unknown

MAP (biallelic pathogenic MUTYH variants)

10 to a few hundred colonic adenomatous polyps

Third decade or later

Unknown

Source: Jasperson, 2017 ; Nielsen, 2021 

Genetics

Genes

APC (NM_000038, NM_001127511 Exon 1b only) and MUTYH (NM_001128425)

For more information, see the Genes Tested table

Penetrance

Classic FAP: 100% incidence of CRC in untreated individuals 

MAP:

  • 43-63% incidence of CRC by age 60 
  • 80-90% lifetime risk of CRC 

Etiology

FAP is estimated to account for 0.5% of CRC cases. 

MAP is estimated to account for 0.7% of all CRC cases. 

Prevalence

FAP: Approximately 1 in 6,850 to 1 in 31,250 individuals have FAP. 

MAP: Approximately 1 in 20,000 to 1 in 60,000 individuals have MAP ; approximately 1% of White individuals are predicted to carry a single pathogenic MUTYH variant. 

Inheritance

APC is autosomal dominant. 

MUTYH is autosomal recessive. 

De Novo Variants

APC : 20-25% of individuals with FAP have a de novo pathogenic variant. 

  • 20% of individuals with apparent de novo variants in APC have somatic mosaicism. 

Test Description

See the Genes Tested table for genes included in the panel.

Methodology

This test is performed using the following sequence of steps:

  • Selected genomic regions, primarily coding exons and exon-intron boundaries from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
  • Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as NGS) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline.
  • Sanger sequencing is performed as necessary to fill in regions of low coverage and, in certain situations, to confirm variant calls.
  • The pipeline includes an algorithm for detection of large (single exon-level or larger) deletions and duplications.
  • Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.

Clinical Sensitivity

Classic FAP: approximately 93% 

  • ≤90% of APC pathogenic variants detected by sequencing 
  • Approximately 8-12% of APC pathogenic variants detected by deletion/duplication testing  

Attenuated FAP: <30% 

GAPPS: unknown 

MAP:

  • Approximately 99% of pathogenic MUTYH variants detected by full gene sequencing 
  • <1% of pathogenic MUTYH variants detected by deletion/duplication analysis 

Analytical Sensitivity

Variant Class Analytical Sensitivity (PPA) Estimatea (%)
and 95% Credibility Region (%)
Analytical Specificity (NPA) (%)

SNVs

>99 (96.9-99.4)

>99.9

Deletions 1-10 bpb

93.8 (84.3-98.2)

>99.9

Insertions 1-10 bpb

94.8 (86.8-98.5)

>99.9

Exon-levelc Deletions

97.8 (90.3-99.8) [2 exons or larger]

62.5 (38.3-82.6) [single exon]

>99.9

Exon-levelc Duplications

83.3 (56.4-96.4) [3 exons or larger]

>99.9

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. These values do not apply to testing performed by multiplex ligation-dependent probe amplification (MLPA).

bVariants greater than 10 bp may be detected, but the analytical sensitivity may be reduced.

cIn most cases, a single exon deletion or duplication is less than 450 bp and 3 exons span a genomic region larger than 700 bp.

bp, base pairs; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants

Testing Strategy

Contraindications for Ordering

  • Should not be ordered to detect somatic variants associated with malignancy as sensitivity for mosaic variants is low with methodology used for germline assays
  • Individuals with hematologic malignancy and/or a previous allogenic bone marrow transplant should not undergo molecular genetic testing on peripheral blood specimen.
    • Testing of cultured fibroblasts is required for accurate interpretation of test results.

Results

Result Variant(s) Detected Clinical Significance

Positive

Single pathogenic variant in APC gene

Predictive of FAP or other APC-associated polyposis condition

Two pathogenic variants in MUTYH gene on opposite chromosomes

Predictive of MAP

Single pathogenic MUTYH variant

Individual is a carrier of MAP and may be affected if another unidentified pathogenic MUTYH variant is present on the opposite chromosome

Possible increased risk for cancer has been associated with a single pathogenic MUTYH variant, but is not well defined

Negative

No pathogenic variants in either APC or MUTYH gene

Does not rule out FAP, other APC-associated polyposis conditions, or MAP

Inconclusive

Variant of uncertain clinical significance detected

Uncertain

Limitations

  • A negative result does not exclude a diagnosis of FAP or MAP.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if this patient has had an allogenic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of targeted genes
    • Regulatory region and deep intronic variants
    • Breakpoints of large deletions/duplications
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Large duplications less than 3 exons in size
    • Noncoding transcripts
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants

Genes Tested

To compare directly to other hereditary cancer panels offered by ARUP Laboratories, see the Hereditary Cancer Panel Comparison table.

Gene MIM Number Disorder/Associated Cancer(s)/Tumor(s) Inheritance

APC

611731

FAP

AFAP

GAPPS

Associated cancer(s)/tumor(s): colorectal adenomas and cancer, duodenal adenomas and cancer, fundic gland polyps, osteomas, thyroid, pancreas, and others

AD

MUTYH

604933

Associated cancer(s)/tumor(s): breast,a colorectala

AD

MAP

Associated cancer(s)/tumor(s): colorectal adenomas and cancer, duodenal adenomas and cancer

AR

aAssociation is suggested but not well-established at this time.

AD, autosomal dominant; AR, autosomal recessive

References

Additional Resources