Germline Genetic Testing Without a Known Tumor
For patients without a known tumor, germline genetic testing should be pursued based on comprehensive family history assessment, with multigene panel testing offered when personal or family history suggests hereditary cancer predisposition, focusing on high-penetrance genes (BRCA1/2, Lynch syndrome genes) as the minimum panel. 1
Key Decision Framework
Step 1: Obtain Detailed Family History
Family history is the cornerstone for determining testing eligibility when no tumor is present. You must document:
- First- and second-degree relatives with cancer diagnoses
- Specific cancer types and ages at diagnosis
- Patient's ethnicity (particularly Ashkenazi Jewish ancestry, which lowers testing thresholds)
- Consanguinity if present 1
This information determines both whether testing is indicated and which genes should be included in the panel.
Step 2: Apply Cancer-Specific Testing Criteria
The decision to test depends on meeting established criteria, which vary by cancer syndrome. While this guideline doesn't define all testing criteria (those are cancer-specific), key populations that warrant testing include:
High-priority scenarios:
- Strong family history of breast/ovarian cancer (multiple affected relatives, early-onset disease)
- Family history suggesting Lynch syndrome (colorectal, endometrial, or other Lynch-associated cancers at young ages or in multiple relatives)
- Multiple family members with pancreatic cancer
- Family history of rare cancers (adrenocortical carcinoma, paragangliomas, medullary thyroid cancer)
- Known pathogenic variant in the family 1
Step 3: Select Appropriate Multigene Panel
When testing is indicated, use multigene panel testing rather than single-gene testing when more than one gene is relevant based on personal/family history. 1
Minimum panel composition: The panel must include high-penetrance genes most relevant to the family history:
- BRCA1 and BRCA2 (given their prevalence and actionability across multiple cancers)
- Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM) - these are reasonable to include in any cancer genetic testing panel 1
- Additional genes based on specific cancer patterns in the family (see Table 1 in guidelines for cancer-specific recommendations) 1
Panel size considerations:
- Focused panels minimize variants of uncertain significance (VUS) and include only well-established genes
- Broader panels may identify unexpected pathogenic variants but increase VUS rates and interpretation complexity
- Broader panels are appropriate when potential benefits are clearly identified and harms from uncertain results can be mitigated 1
Critical Pitfalls to Avoid
1. Testing without adequate family history: Family history is essential for proper interpretation of results, even when broad panels are used. A negative test doesn't eliminate risk if family history is strong. 1
2. Over-reliance on guidelines alone: Current NCCN and other criteria-based testing approaches miss a substantial proportion of pathogenic variant carriers. Studies show 29-64% of patients with pathogenic variants in common and rare cancers, respectively, did not meet NCCN guidelines at time of testing. 2 However, without a tumor to guide testing, family history remains the primary indicator.
3. Misinterpreting VUS: Variants of uncertain significance should not drive clinical management. Larger panels increase VUS detection, which can lead to patient anxiety and inappropriate interventions. 1
4. Testing low-penetrance genes without context: Some genes (like SDHA) have low penetrance and should only be considered actionable with specific personal or family history of associated tumors. 3
Genetic Counseling Considerations
Access to genetic expertise is essential for:
- Proper test selection based on family history
- Interpretation of results, particularly positive findings or VUS
- Facilitating cascade testing in families with identified pathogenic variants
- Addressing psychosocial aspects 1
While oncologists increasingly initiate testing, genetic counseling should be available for complex cases and result interpretation, even if pre-test counseling is not always required. 1
Special Populations
Ashkenazi Jewish ancestry: Lower threshold for BRCA1/2 testing due to founder mutations (particularly BRCA2 c.5946delT). 4, 5
Families with known pathogenic variants: Any family member of someone with a known pathogenic variant warrants testing for that specific variant, regardless of other risk factors. 6
Important Nuance
This guideline assumes appropriate criteria have been met for testing. The scope explicitly does not define which patients should receive germline testing without cancer—those criteria are best handled in cancer- or syndrome-specific guidelines. 1 The recommendation here is that once the decision to test has been made based on family history and established criteria, multigene panel testing should be offered with the gene selection guided by the framework above.