Hereditary Gastrointestinal Cancer Panel, Including Lynch Syndrome

Indication for testing:
  • Recommended test to confirm a diagnosis of hereditary GI cancer in individuals with a personal or family history of GI cancer and/or polyposis.
  • When a relative has a previously identified pathogenic sequence variant, see Familial Mutation, Targeted Sequencing (2001961).
Indication for testing:
  • Recommended test if there is a known familial sequence variant previously identified in a family member.
  • A copy of the family member’s test result documenting the familial variant is required.

Pathogenic 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 similar cancers in a single individual or in a closely related family member. Pathogenic variants in the genes analyzed by this panel cause variable phenotypes and cancer risks, including non-GI cancers. Lynch syndrome, the most common hereditary predisposition to colon cancer, is caused by pathogenic variants in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes.

Disease Overview

Associated Disorder

Lynch syndrome

Individuals with Lynch syndrome are at increased risk for colorectal, endometrial, stomach, ovarian, and other cancers.

Etiology

At least 2-4% of colorectal cancers are associated with a hereditary cause.

Prevalence

  • 1/440 individuals from the general population are estimated to have Lynch syndrome.
  • Prevalence of pathogenic variants in the additional genes on this panel is largely unknown.

Inheritance

  • All genes tested on the Hereditary GI Cancer Panel are autosomal dominant with the exception of:
    • SDHD – autosomal dominant with paternal parent-of-origin effect
    • MUTYH – autosomal recessive but may also have autosomal dominant risks that are not well defined
    • MSH3 and NTHL1 – autosomal recessive
  • Some genes are associated with autosomal recessive childhood cancer predisposition or other syndromes.

Test Description

See Genes Tested table for genes included in the panel.

Clinical Sensitivity

  • Variable, dependent on phenotype/condition
  • Proportion of Lynch syndrome attributed to pathogenic variants in specific mismatch repair (MMR) gene:
    • MLH1 – 50% 
    • MSH2 – 40% 
    • MSH6 – 7-10%   
    • PMS2 – <5% 
    • EPCAM – ~1-3% 

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 hematological 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.
  • When a relative has a previously identified pathogenic variant, see Familial Mutation, Targeted Sequencing (2001961).

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
    • Noncoding transcripts
    • The following exons are not sequenced due to technical limitations of the assay:
      • CHEK2 (NM_001349956) 4; (NM_001005735) 3; (NM_007194) 10,12,13,14,15
      • SDHC (NM_001035511) 5
      • SDHD (NM_001276506) 4
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Deletions/duplications less than 1kb in the targeted genes by array
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants
    • Single exon deletions/duplications in the following exons:
      • APC (NM_001127511) 1
      • BMPR1A (NM_004329) 9
      • CDH1 (NM_004360) 1
      • CHEK2 (NM_001005735) 3; (NM_007194) 11, 12, 14, 15
      • MSH2 (NM_000251) 1; (NM_001258281) 2
      • MSH6 (NM_000179) 10
      • MUTYH (NM_001128425) 1
      • NTHL1 (NM_002528) 3, 4, 5, 6
      • POLD1 (NM_002691) 6, 18, 25
      • PTEN (NM_000314) 8, 9; (NM_001304717) 1
      • SDHD (NM_001276506) 4
      • TP53 (NM_001126113) 10; (NM_001126114) 10

Analytical Sensitivity

  • For Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) of PMS2: 99%
  • For massively parallel sequencing:
Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

100

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

100

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

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

Genes Tested

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

APC

611731

Familial adenomatous polyposis (FAP)

Attenuated FAP (AFAP)

Associated cancer(s)/tumor(s): colon, duodenal, thyroid, pancreas, stomach, medulloblastoma, hepatoblastoma

AD

AXIN2

604025

Oligodontia-colorectal cancer syndrome (OSCRCS)

Associated cancer(s): colona

AD

BMPR1A

601299

Juvenile polyposis syndrome (JPS)

Associated cancer(s)/tumor(s): colon, stomach, small intestine, pancreas

AD

CDH1

192090

Hereditary diffuse gastric cancer (HDGC)

Associated cancer(s)/tumor(s): diffuse gastric, lobular breast

AD

CHEK2

604373

Associated cancer(s)/tumor(s): breast, colorectal,a prostate,a thyroida

AD

EPCAM 185535

Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC)

Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, and others

AD

MLH1

120436

Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC)

Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, and others

AD

Constitutional mismatch repair deficiency (CMMRD)

AR

MSH2

609309

Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC)

Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, and others

AD

Constitutional mismatch repair deficiency (CMMRD)

AR

MSH3

600887

Associated cancer(s)/tumor(s): polyposisa

AR

MSH6

600678

Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC)

Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, and others

AD

Constitutional mismatch repair deficiency (CMMRD)

AR

MUTYH

604933

Associated cancer(s)/tumor(s): breasta

AD

MUTYH-associated polyposis (MAP)

Associated cancer(s)/tumor(s): colon, duodenal

AR

NTHL1

602656

Associated cancer(s)/tumor(s): polyposisa

AR

PMS2

600259

Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC)

Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, and others

AD

Constitutional mismatch repair deficiency (CMMRD)

AR

POLD1

174761

Polymerase proofreading-associated polyposis (PPAP)

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

AD

POLE

174762

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

AD

PTEN

601728

Cowden syndrome/PTEN hamartoma tumor syndrome

Associated cancer(s)/tumor(s): breast, endometrial, thyroid, colon, renal cell carcinoma

AD

SDHB

185470

Associated cancer(s)/tumor(s): paraganglioma, pheochromocytoma, GIST, pulmonary chondroma, renal clear cell carcinoma

AD

SDHC

602413

Associated cancer(s)/tumor(s): paraganglioma, pheochromocytoma, GIST, pulmonary chondroma, renal clear cell carcinoma

AD

SDHD

602690

Associated cancer(s)/tumor(s): paraganglioma, pheochromocytoma, GIST, pulmonary chondroma, renal clear cell carcinoma

ADb

SMAD4

600993

Juvenile polyposis syndrome (JPS); hereditary hemorrhagic telangiectasia (HHT) syndrome

Associated cancer(s)/tumor(s): colon, stomach, small intestine, pancreas

AD

STK11

602216

Peutz-Jeghers syndrome (PJS)

Associated cancer(s)/tumor(s): breast, colon, stomach, small intestine, pancreas, ovary, testes, lung

AD

TP53

191170

Li-Fraumeni syndrome (LFS)

Associated cancer(s)/tumor(s): soft tissue sarcoma, osteosarcoma, central nervous system (CNS) tumor, breast, adrenocortical carcinoma, choroid plexus carcinoma, rhabdomyosarcoma

AD

aAssociation is suggested but not well-established at this time

bPaternal parent-of-origin effect

AD, autosomal dominant; AR, autosomal recessive

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