Hereditary Gastrointestinal Cancer

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

  • Germline analysis of genes associated with high-risk hereditary colorectal cancer syndromes (including Lynch syndrome, familial adenomatous polyposis [FAP]/other APC-associated polyposis condition, or MUTYH-associated polyposis [MAP])
    • Note: For suspected Lynch syndrome, the recommended test is Lynch Syndrome Panel, Sequencing and Deletion/Duplication (3001605), which has a higher clinical sensitivity.
  • Testing minors for adult-onset conditions is not recommended; testing will not be performed in minors without prior approval. For additional information, please contact an ARUP genetic counselor at 800-242-2787 ext. 2141.
  • Recommended test to confirm a diagnosis of hereditary GI cancer in individuals with a personal or family history of GI cancer and/or polyposis
  • Testing minors for adult-onset conditions is not recommended; testing will not be performed in minors without prior approval. For additional information, please contact an ARUP genetic counselor.
  • 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.

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.

Genes Included in ARUP Hereditary Colorectal and GI Cancer Tests
Gene Lynch Syndrome Panel, Sequencing and Deletion/Duplication 3001605 Hereditary Gastrointestinal Cancer High-Risk Panel, Sequencing and Deletion/Duplication 3005697 Hereditary Gastrointestinal Cancer Panel, Sequencing and Deletion/Duplication 2013449

EPCAM

MLH1

MSH2

MSH6

PMS2

APC

 

MUTYH

 

AXIN2

 

 

BMPR1A

 

 

CDH1

 

 

CHEK2

 

 

KIT

 

 

MLH3

 

 

MSH3

 

 

NTHL1

 

 

PDGFRA

 

 

POLD1

 

 

POLE

 

 

PTEN

 

 

SDHA

 

 

SDHB

 

 

SDHC

 

 

SDHD

 

 

SMAD4

 

 

STK11

 

 

TP53

 

 

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:
Gene Inheritance Pattern

SDHD

Autosomal dominant with paternal parent-of-origin effect

MLH3

Autosomal recessive

MSH3

Autosomal recessive

NTHL1

Autosomal recessive

MUTYH

Autosomal recessive but may also have autosomal dominant risks that are not well defined

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

Test Interpretation

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

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

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

Exon-level deletions/duplications (MLPA)

>99

>99

aPPA values are derived from larger methods-based MPS and/or Sanger validations. These values do not apply to testing performed by multiplex ligation-dependent probe amplification (MLPA) unless otherwise indicated.

bVariants greater than 10 bp may be detected, but the analytic 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

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.

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

APC

611731

FAP

AFAP

GAPPS

Colorectal adenomas and cancer, duodenal adenomas and cancer, gastric fundic gland polyps, medulloblastoma, osteomas, pancreas, thyroid, and others

AD

AXIN2

604025

ODCRCS

Colorectal,a polyposis

AD

BMPR1A

601299

JPS

Colorectal, juvenile polyps, small intestine, stomach

AD

CDH1

192090

HDGC

Diffuse gastric, lobular breast

AD

CHEK2

604373

Breast, colorectal, prostate, thyroida

AD

EPCAM

(Exon 9 deletions/duplications only)

185535

Lynch syndrome/HNPCC

Brain, colorectal, endometrial, ovarian, pancreas, prostate, renal pelvis and/or ureter, stomach, and others

AD
KIT 164920 GIST AD

MLH1

120436

Lynch syndrome/HNPCC

Brain, colorectal, endometrial, ovarian, pancreas, prostate, renal pelvis and/or ureter, stomach, and others

AD

CMMRD

AR

MLH3 604395

MLH3-associated polyposis

Breast,a colorectal,a polyposis

AR
MSH2

609309

Lynch syndrome/HNPCC

Brain, colorectal, endometrial, ovarian, pancreas, prostate, renal pelvis and/or ureter, stomach, and others

AD

CMMRD

AR

MSH3

600887

Colorectal,a polyposis

AR

MSH6

600678

Lynch syndrome/HNPCC

Brain, colorectal, endometrial, ovarian, pancreas, prostate, renal pelvis and/or ureter, stomach, and others

AD

CMMRD

AR

MUTYH

604933

Breast,a colorectala

AD

MAP

Colorectal adenomas and cancer, duodenal adenomas and cancer

AR

NTHL1

602656

Colorectal,a polyposis

AR

PDGFRA 173490 GIST, inflammatory fibroid polyp, fibroid tumor AD

PMS2

600259

Lynch syndrome/HNPCC

Brain, colorectal, endometrial, ovarian, pancreas, prostate, renal pelvis and/or ureter, stomach, and others

AD

CMMRD

AR

POLD1

174761

PPAP

Colorectal,a polyposis

AD

POLE

174762

PPAP

Colorectal,a polyposis

AD

PTEN

601728

Cowden syndrome/PTEN hamartoma tumor syndrome

Breast, colorectal, endometrial, Lhermitte-Duclos disease (cerebellar dysplastic gangliocytoma), melanoma, renal cell carcinoma, thyroid, and others

AD

SDHA 600857

HPP syndromes

GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, renal clear cell carcinoma
AD

SDHB

185470

HPP syndromes

GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, renal clear cell carcinoma

AD

SDHC

602413

HPP syndromes

GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, renal clear cell carcinoma

AD

SDHD

602690

HPP syndromes

GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, renal clear cell carcinoma

ADb

SMAD4

600993

JPS, HHT syndrome

Colorectal, juvenile polyps, small intestine, stomach

AD

STK11

602216

PJS

Breast, cervix, colorectal, endometrial, lung, ovarian (sex cord with annular tubules), pancreas, Peutz-Jeghers-type hamartomatous polyps, small intestine, stomach, testes

AD

TP53

191170

LFS

Adrenocortical carcinoma, breast, choroid plexus carcinoma, CNS, colorectal, melanoma, osteosarcoma, pancreas, prostate, renal, rhabdomyosarcoma, soft tissue sarcoma, stomach, thyroid, and others

AD

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

bPaternal parent-of-origin effect.

AD, autosomal dominant; AFAP, attenuated familial adenomatous polyposis; AR, autosomal recessive; CMMRD, constitutional mismatch repair deficiency; CNS, central nervous system; FAP, familial adenomatous polyposis; GAPPS, gastric adenocarcinoma and proximal polyposis of the stomach; GIST, gastrointestinal stromal tumors; HDGC, hereditary diffuse gastric cancer; HHT, hereditary hemorrhagic telangiectasia; HNPCC, hereditary nonpolyposis colorectal cancer; HPP, hereditary paraganglioma-pheochromocytoma; JPS, juvenile polyposis syndrome; LFS, Li-Fraumeni syndrome; MAP, MUTYH-associated polyposis; ODCRCS, oligodontia-colorectal cancer syndrome; PJS, Peutz-Jeghers syndrome; PPAP, polymerase proofreading-associated polyposis

References

Additional Resources