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APC – genetic testing

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  • A person who fulfils criteria for polyposis panel testing
  • A person with an intra-abdominal or abdominal wall desmoid tumour over age 10 years
  • A person with hepatoblastoma
  • A person with congenital hypertrophy of the retinal pigment epithelium (CHRPE) with atypical features (bilateral, multifocal and in multiple quadrants, pisiform shape, irregular borders)rr
  • A person who has a relative with an APC pathogenic variant

Genetic testing is essential for good clinical care of individuals who are suspected of having a heritable pathogenic variant in this gene.

The results of the following investigations may significantly influence the likelihood of detecting a heritable pathogenic variant in the APC gene: 

  • the cumulative number of adenomatous colorectal polyps
  • testing for (biallelic) pathogenic variants in MUTYH
  • detection of a somatic pathogenic variant in the CTNNB1 (beta-catenin) gene in desmoid-type fibromatosis (available evidence indicates somatic CTNNB1 and germline APC pathogenic variants are mutually exclusiver).

In unselected individuals with colorectal cancer the frequency of APC germline pathogenic variants is <0.2%.r

Approximately 60% of patients with >100 adenomas have an APC pathogenic variant identified (and of the APC negatives ~16% have biallelic MUTYH pathogenic variants).r

Approximately 10% of patients with an attenuated FAP phenotype (20-100 adenoma) have an APC pathogenic variant identified (and of the APC negatives ~8% have biallelic MUTYH pathogenic variants).r

About 15-20% of APC pathogenic variants arise de novo.r

Factors Probability of detecting a heritable pathogenic variant
More than 1000 adenomatous polyps 80%r
Between 100 and 1000 adenomatous polyps 56%r
Between 20 and 100 adenomatous polyps 10%r
Between 10 and 20 adenomatous polyps 5%r
Extra-colonic manifestations (when colorectal polyp status is unknown):  
  • cribriform-morular variant of papillary thyroid carcinoma
 Unknown but increasedr
  • hepatoblastoma and no family history of FAP
 ~7%r
  • desmoid-type fibromatosis diagnosed over age 10 years:
 
  • all sites combined
 7.5%r
 
  • intra-abdominal/abdominal wall
 12.2%r​
 
  • extra-abdominal
 1.6%r​
  • desmoid-type fibromatosis (any location) diagnosed under age 10 years
 Unknown
  • multiple and/or bilateral CHRPE at any age
 Unknown
  • multiple osteomas of the skull or mandible
 Unknown
Patient has a first or second degree relative with documented pathogenic variant Up to 50%

CHRPE - congenital hypertrophy of the retinal pigment epithelium

Colorectal polyposis due to non-adenomatous polyps (e.g. serrated, hamartomatous, juvenile etc).

Colorectal polyposis due to polyps of mixed histology where the non-adenomatous polyps predominate (e.g. significant numbers of both serrated and adenomatous polyps).

Person with solitary classical CHRPE or with congenital grouped pigmentation of the retina (“bear tracks”).rr

A variant-specific test (rather than sequencing a single gene or gene panel) may be more cost effective and appropriate where:

  • a known pathogenic variant has been identified in a relative
  • a specific pathogenic variant has been identified on somatic tumour testing.

Predictive testing should never be ordered when only a variant of uncertain significance or a benign/likely benign variant has been identified in a family.

A range of testing methodologies is needed to identify pathogenic changes in the APC gene including:

  • sequencing
  • copy number analysis (e.g. MLPA)

Information about DNA tests and testing laboratories is available from: 

If a decision is made to test this gene as part of a cancer gene panel, care should be taken to select a panel where the individual genes tested have both clinical validity and clinical utility.

If this gene is tested using genomic sequencing (“next generation sequencing” or NGS), and testing has not identified a pathogenic variant, the value of testing using another methodology (e.g. MLPA, Sanger sequencing) should be considered.

If genetic testing in DNA from peripheral blood is uninformative, testing of two or more different tumour samples may be indicated to assess for mosaicism. 

Result Reference databases Considerations and advice
Pathogenic variant search
Pathogenic variant

ClinVar

UMD

LOVD

InSight

HGMD

DMuDB

 APC (Familial adenomatous polyposis) – risk management
Variant of uncertain significance Review pathogenicity of variants periodically
Identify other genes for which a pathogenic variant search could be considered
No reportable variant   Identify other genes for which a pathogenic variant search could be considered
Predictive testing
Family pathogenic variant identified   APC (Familial adenomatous polyposis) – risk management
Family pathogenic variant not found   Screening based on revised risk estimate

If a pathogenic variant is identified refer to a clinical genetics service or familial cancer centre for review, family risk notification and predictive testing.

If a mosaic pathogenic variant is identified refer to a clinical genetics service or familial cancer centre for review and guidance about the penetrance of phenotypic features (including cancer risk).

For additional information about the management of genetic test results when ordered by a non-genetic healthcare professional refer to eviQ’s Guide for health professionals ordering genetic testing.

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Bibliography

Crago, A.M., J. Chmielecki, M. Rosenberg, et al. 2015. "Near universal detection of alterations in CTNNB1 and Wnt pathway regulators in desmoid-type fibromatosis by whole-exome sequencing and genomic analysis." Genes Chromosomes Cancer 54(10):606-615.

CTNNB1 mutations or APC abnormalities have been observed in approximately 85% of desmoids examined by Sanger sequencing and are associated with Wnt/beta-catenin activation. We sought to identify molecular aberrations in "wild-type" tumors (those without CTNNB1 or APC alteration) and to determine their prognostic relevance. CTNNB1 was examined by Sanger sequencing in 117 desmoids; a mutation was observed in 101 (86%) and 16 were wild type. Wild-type status did not associate with tumor recurrence. Moreover, in unsupervised clustering based on U133A-derived gene expression profiles, wild-type and mutated tumors clustered together. Whole-exome sequencing of eight of the wild-type desmoids revealed that three had a CTNNB1 mutation that had been undetected by Sanger sequencing. The mutation was found in a mean 16% of reads (vs. 37% for mutations identified by Sanger). Of the other five wild-type tumors sequenced, two had APC loss, two had chromosome 6 loss, and one had mutation of BMI1. The finding of low-frequency CTNNB1 mutation or APC loss in wild-type desmoids was validated in the remaining eight wild-type desmoids; directed miSeq identified low-frequency CTNNB1 mutation in four and comparative genomic hybridization identified APC loss in one. These results demonstrate that mutations affecting CTNNB1 or APC occur more frequently in desmoids than previously recognized (111 of 117; 95%), and designation of wild-type genotype is largely determined by sensitivity of detection methods. Even true CTNNB1 wild-type tumors (determined by next-generation sequencing) may have genomic alterations associated with Wnt activation (chromosome 6 loss/BMI1 mutation), supporting Wnt/beta-catenin activation as the common pathway governing desmoid initiation.

Spier, I., D. Drichel, M. Kerick, et al. 2016. "Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases." J Med Genet 53(3):172-179.

BACKGROUND: In 30-50% of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, or POLE or POLD1, causing polymerase-proofreading-associated polyposis can be identified, although a hereditary aetiology is likely. This study aimed to explore the impact of APC mutational mosaicism in unexplained polyposis. METHODS: To comprehensively screen for somatic low-level APC mosaicism, high-coverage next-generation sequencing of the APC gene was performed using DNA from leucocytes and a total of 53 colorectal tumours from 20 unrelated patients with unexplained sporadic adenomatous polyposis. APC mosaicism was assumed if the same loss-of-function APC mutation was present in >/= 2 anatomically separated colorectal adenomas/carcinomas per patient. All mutations were validated using diverse methods. RESULTS: In 25% (5/20) of patients, somatic mosaicism of a pathogenic APC mutation was identified as underlying cause of the disease. In 2/5 cases, the mosaic level in leucocyte DNA was slightly below the sensitivity threshold of Sanger sequencing; while in 3/5 cases, the allelic fraction was either very low (0.1-1%) or no mutations were detectable. The majority of mosaic mutations were located outside the somatic mutation cluster region of the gene. CONCLUSIONS: The present data indicate a high prevalence of pathogenic mosaic APC mutations below the detection thresholds of routine diagnostics in adenomatous polyposis, even if high-coverage sequencing of leucocyte DNA alone is taken into account. This has important implications for both routine work-up and strategies to identify new causative genes in this patient group.

Version 7

Date Summary of changes
19/09/2022

Protocol updated to align with the publishing of ID 4116 Gastrointestinal polyposis and colorectal cancer –panel testing. Approved for publishing with the following changes made to the target population:

  • Removed bullet 1: 'A person with 10 or more adenomatous colorectal polyps (cumulative count) before age 30 years'
  • Removed bullet 2: 'A person with >20 adenomatous colorectal polyps (cumulative count) by age 60'
  • Replaced above with 'A person who fulfils criteria for polyposis panel testing' and a link to ID 4116

Version increased to V.7. Review at next scheduled review date.

Version 6

Date Summary of changes
13/01/2021

Protocol reviewed at October 2019 cancer genetics reference committee meeting. Discussion continued via email. Approved for publication with the following changes made:

Target population: completely replaced.

Investigations before genetic testing: 

  • New bullet inserted: 'testing for (biallelic) pathogenic variants in MUTYH'
  • Two bullets deleted: 
    • 'where multiple colorectal adenomas are documented in an isolated family member (i.e. apparently sporadic adenomatous polyposis) consider also testing for homozygous recessive mutations in MUTYH
    • where multiple colorectal adenomas are documented in 2 or more full-sibs in the absence of a family history consider testing for homozygous recessive mutations in MUTYH'
  • Final bullet: 'in a desmoid tumour' changed to 'in desmoid-type fibromatosis'.

Probability of a heritable pathogenic variant and factors table: completely replaced.

Circumstances in which testing is not indicated: 

  • Deleted 'Evidence of mismatch repair deficiency within colorectal carcinoma or polyp.'
  • 'Colorectal polyposis due to polyps of mixed histology (e.g. significant numbers of both serrated and adenomatous polyps).' changed to read: 'Colorectal polyposis due to polyps of mixed histology where the non-adenomatous polyps predominate (e.g. significant numbers of both serrated and adenomatous polyps).'
  • 'Person with isolated, single CHRPE (congenital hypertrophy of the retinal pigment epithelium) after review by an ophthalmologist.' changed to read: 'Person with solitary classical CHRPE or with congenital grouped pigmentation of the retina (“bear tracks”).1,2'

​Testing methods: Resources list updated.

The following sections of the document were updated to align with the new eviQ cancer genetics genetic testing template:​

  • ‘Unclassified variant’ changed to ‘variant of uncertain significance’ throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs
  • "Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up
  • Related pages: added link to "Guide for health professionals ordering genetic testing". Removed link to "Pre-test counselling"
  • Probability of a heritable pathogenic variant: last row of table - probability changed from "25-50%" to "Up to 50%"
  • Circumstances in which testing is not indicated: template wording updated
  • Testing methods: template wording updated
  • Result interpretation: table format updated. Reference databases added. Template sentence added (including link to "Guide for health professionals ordering genetic testing")
  • Counselling: section deleted.

Version number changed to V.6. Review in two years.
10/11/2021 Removed link to "European Directory of DNA Diagnostic Laboratories"

Version 5

Date Summary of changes
13/08/2010 Published
05/09/2011 Reviewed at September reference committee meeting no changes to document.
02/04/2014

Discussed at August 2012 reference committee meeting, review continued via email and the following changes made:

  • Placed into new format.
  • Target population - updated.
  • Investigations which should be considered before germline genetic testing - updated.
  • Factors which influence the pre-test probability of a heritable mutation including table - updated.
  • Circumstances in which testing is not indicated - updated.
  • Diagnostic testing - Link to Human Genetics Society of Australasia removed as per discussion at March 5 2014 reference committee meeting.
  • Websites - updated.
  • References - updated.
  • Review second yearly.
30/09/2015 Sentence added to Genetic Testing protocol template: if a decision is made to test this gene(s) as part of a cancer gene panel, care should be taken to select a panel where the individual genes tested have both clinical validity and clinical utility.
20/02/2017

Protocol reviewed at the October 2016 RC meeting and the following changes made:

  • Target population - wording updated
  • Investigations which should be considered - updated
  • Factors which influence the pre-test probability of a heritable - updated
  • Diagnostic testing - updated to new format
  • References - updated
  • Changed to version 3
  • Next review in 2 years. 
31/05/2017 Transferred to new eviQ website. Version number changed to V.4.
01/06/2018
  • 'Gene Tests' link in Testing Methods section relabelled as GeneReviews.
  • Removed link to the Clinical molecular genetics society best practice guidelines in Result Interpretation section, as webpage no longer available.
28/08/2019 Protocol title changed from 'Genetic testing for heritable mutations in the APC gene' to 'APC genetic testing' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.5.

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/746

05 Feb 2023