What triggers investigation for germline (genetic) mutations?

Triggers for Investigation of Germline Mutations

Germline mutation testing should be performed in patients with personal or family history suggestive of hereditary cancer syndromes, specific tumor characteristics indicating potential germline origin, and when tumor genomic profiling reveals potentially pathogenic variants in cancer predisposition genes. 1

Primary Indications for Germline Mutation Testing

Personal and Family History Factors

• Personal history of cancer with features suggestive of hereditary syndromes:

  • Early age of onset (e.g., <40 years for CLL) 1
  • Multiple primary cancers in the same individual
  • Rare cancers associated with known hereditary syndromes (e.g., sarcomas in Li-Fraumeni syndrome) 2

• Family history suggestive of hereditary cancer syndromes:

  • Multiple relatives with cancer, especially of the same or related types
  • Cancer in multiple generations following autosomal dominant pattern
  • Known cancer predisposition syndrome in the family (e.g., Li-Fraumeni syndrome, Lynch syndrome) 1

Tumor-Specific Characteristics

• Specific tumor types with high hereditary component:

  • GIST tumors lacking KIT or PDGFRA mutations (consider SDH gene testing) 1
  • Desmoid tumors (evaluate for FAP or Gardner syndrome) 1
  • Microsatellite instability in tumors (consider Lynch syndrome) 1

• Tumor genomic profiling findings:

  • Pathogenic variants in cancer predisposition genes identified in tumor testing 1
  • Variant allele frequency (VAF) of approximately 50% in tumor sequencing, suggesting possible germline origin 1
  • Founder mutations identified in tumor-only sequencing (e.g., BRCA2 c.5946delT in Ashkenazi Jewish patients) 1

Special Considerations by Cancer Type

Hematologic Malignancies

• For chronic lymphocytic leukemia (CLL):
  • Exceptionally young age of onset (<40 years) 1
  • Presence of family/personal history of Li-Fraumeni-associated cancers 1
  • Variants with preserved functionality detected in TP53 gene (may indicate germline origin) 1

Solid Tumors

• For extrahepatic cholangiocarcinoma (eCCA):

  • Personal/family cancer history suggestive of hereditary syndromes
  • Microsatellite instability identified in tumor testing 1
  • Genetic alterations potentially linked with hereditary syndromes 1

• For soft tissue sarcomas:

  • Personal/family history suggestive of Li-Fraumeni syndrome 1
  • Malignant peripheral nerve sheath tumors (consider NF1/NF2 testing) 1

Important Caveats and Considerations

Limitations of Tumor-Only Testing

• Approximately 8-10% of germline pathogenic variants are missed on tumor testing 1
• Tumor-only sequencing may not detect:
  • Copy number variants
  • Intronic variants
  • Large structural variants
  • Repetitive element insertions 1

Avoiding Common Pitfalls

• Do not rely exclusively on tumor testing for germline variant detection - dedicated germline testing is necessary even with negative tumor results 1
• Do not use dbSNP alone for filtering polymorphisms - many variants listed in dbSNP exhibit loss of function despite not being reported as pathogenic in ClinVar 1
• Do not dismiss testing in patients who don't meet traditional criteria - significant proportions of patients (up to 49%) with germline pathogenic variants may not meet standard guideline-based criteria 1

Verification of Germline Origin

• When germline origin is suspected, confirm with testing of non-tumor tissue:
  • CD3+ cells/CD19-negative fraction (for hematologic malignancies)
  • Saliva or buccal swab (with caution regarding potential tumor cell contamination)
  • Skin biopsy (gold standard for hematologic malignancies) 1
• VAF >30% for SNVs or >20% for small insertions/deletions in non-tumor tissue suggests germline origin 1

By following these guidelines for germline mutation testing, clinicians can identify patients with hereditary cancer syndromes, enabling appropriate management strategies for both the patient and at-risk family members.