Hereditary Gastrointestinal Cancer

Pathogenic germline variants in multiple genes have been implicated in hereditary gastrointestinal (GI) cancer. Hereditary cancer predisposition is often characterized by early age of onset (typically before age 50) and multiple, multifocal, and/or related cancers in a single individual or in closely related family member(s). Pathogenic variants in some genes analyzed by these panels cause variable phenotypes and cancer risks, including non-GI cancers. See the Genes Tested table below for more details regarding the genes and syndromes included on both the Hereditary Colorectal cancer High-Risk Panel and the Hereditary Gastrointestinal Cancer Panel. Genes included on these panels are also included on other related tests (see Related Tests section and Hereditary Cancer Genetic Testing - Germline Testing for Inherited Cancer Syndromes).

Disease Overview

Associated Disorders

APC-Associated Polyposis Conditions

• Familial adenomatous polyposis (FAP), attenuated FAP, and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) 
• Caused by a single pathogenic variant in the APC gene 
• Classic FAP is characterized by the development of hundreds to thousands of adenomatous colonic polyps with a 100% lifetime risk of colorectal cancer in untreated individuals. 

Lynch Syndrome

• Caused by a single pathogenic variant in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or EPCAM exon 9 deletions
• Individuals are at an increased risk for colorectal (up to approximately 60%), uterine, and other cancers.
• The Lynch syndrome genes are also offered through the Lynch Syndrome Panel (3001605); for more information, see the Lynch Syndrome Panel, Sequencing and Deletion/Duplication Test Fact Sheet.

MUTYH-Associated Polyposis

• Caused by biallelic pathogenic variants in the MUTYH gene 
• Colon polyps are less numerous (typically 10-100s) than classic FAP 
• Estimated 80-90% lifetime risk of colorectal cancer in untreated individuals 

Others

• See the Genes Tested table for more details regarding the additional genes and syndromes included on the Hereditary Gastrointestinal Cancer Panel.

Genetics

Genes

For information about the Lynch syndrome panel, see the Lynch Syndrome Panel, Sequencing and Deletion/Duplication Test Fact Sheet.

See the Genes Tested table for detailed information for each gene included on these panels.

Etiology

Greater than 2-4% of colorectal cancers are associated with a hereditary cause. 

Prevalence

• The prevalence of Lynch syndrome has been estimated to be 1/279 individuals from the general population. 
• The prevalence of FAP has been estimated to be between 1 in 6,850 to 1 in 31,250 live births. 
• The prevalence of MAP is estimated to be between 1 in 20,000 to 1 in 60,000 individuals. 

Inheritance

• All genes tested on the panels covered by this document are autosomal dominant with the exception of the following:

• Some genes are associated with autosomal recessive childhood cancer predisposition or other syndromes.
• See the Genes Tested table for additional details.

Contraindications for Ordering

• Individuals with a suspected diagnosis of Lynch syndrome should consider the Lynch Syndrome Panel, Sequencing and Deletion/Duplication (3001605) due to inclusion of the recurrent MSH2 inversion and an increased detection of single exon deletions/duplications.
• 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 allogeneic 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.
• When a relative has a previously identified pathogenic variant, see Familial Targeted Sequencing (3005867).

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 next generation sequencing [NGS]) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline. The pipeline includes an algorithm for detection of large (single exon-level or larger) deletions and duplications.
• Sanger sequencing is performed as necessary to fill in regions of low coverage and in certain situations, to confirm variant calls.
• Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.
• Long-range PCR followed by nested Sanger sequencing is performed on the following gene and exons:
  • PMS2 (NM_000535) 11, 12, 13, 14, 15
• Bidirectional Sanger sequencing is performed on the following genes and exons:
  • MSH2 (NM_000251) 5
  • PMS2 (NM_000535) 7
  • PTEN (NM_000314) 9
• Multiplex ligation-dependent probe amplification (MLPA) is performed on the following gene to call exon-level deletions and duplications:
  • PMS2 (NM_000535)

Clinical Sensitivity

Variable, dependent on phenotype/condition

Analytic Sensitivity

Limitations

• A negative result does not exclude a heritable form of cancer.
• Diagnostic errors can occur due to rare sequence variations.
• Interpretation of this test result may be impacted if this individual has had an allogeneic stem cell transplantation.
• The following will not be evaluated:
  • Variants outside the coding regions and intron-exon boundaries of the targeted genes
  • Regulatory region variants and deep intronic variants
  • Breakpoints of large deletions/duplications
  • Deletions/duplications in AXIN2 and MSH3
  • Sequence variants in EPCAM
  • The following exons are not sequenced due to technical limitations of the assay:
    • APC (NM_001354896) 12; (NM_001354898, NM_001354904) 2; (NM_001354900) 11
    • CHEK2 (NM_001005735) 3; (NM_001349956) 4
    • PDGFRA (NM_001347827) 17; (NM_001347828) 2; (NM_001347830) 1
    • SDHA (NM_004168) 14; (NM_001294332) 13; (NM_001330758) 12
    • SDHC (NM_001035511) partial exon 5 (Chr1:161332225-161332330); (NM_001278172) partial exon 4 (Chr1:161332225-161332330)
    • SDHD (NM_001276506) 4
• The following may not be detected:
  • Deletions/duplications/insertions of any size by MPS
  • Large duplications less than 3 exons in size
  • Noncoding transcripts
  • Single exon deletions/duplications may not be detected based on the breakpoints of the rearrangement
  • Some variants due to technical limitations in the presence of pseudogenes and/or repetitive/homologous regions
  • Low-level somatic variants
  • Deletions/duplications in the following exons:
    • APC (NM_001354896) 12; (NM_001354898, NM_001354904) 2; (NM_001354900) 11
    • BMPR1A (NM_004329) 12-13
    • CDH1 (NM_001317185) 10
    • CHEK2 (NM_007194) 11-15; (NM_001005735) 3,12-16; (NM_001257387) 12-16; (NM_001349956) 4,10-14; (NM_145862) 10-14
    • MLH3 (NM_001040108) 7-8; (NM_014381) 7
    • PDGFRA (NM_001347827) 17; (NM_001347828) 2; (NM_001347830) 1
    • PTEN (NM_000314, NM_001304718) 9; (NM_001304717) 1,10
    • SDHA (NM_004168) 1,10-15; (NM_001294332) 1,9-14; (NM_001330758) 1,10-13
    • SDHD (NM_001276506) 4

Genes Tested

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