Hereditary Gastrointestinal Cancer Panel, Including Lynch Syndrome

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.

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:

Genes Tested