Indications for Genetic Testing for Inherited Cancer Risk After Biomarker Testing

Summary: This resource lists the general risk factors and indications for genetic testing for inherited cancer risk that should be considered for patients with cancer. See cancer-specific guidelines for more detail about genetic testing for inherited cancer risk criteria.

By JAX Clinical Education | October 2025 

Determining when genetic testing for inherited cancer risk after biomarker testing is warranted requires assessing information from the test report as well as patient factors.

1. Test type: Somatic, paired somatic-germline, or concurrent somatic + germline

Interpretation of potential germline variants depends on the type of cells tested in the biomarker test: cancer cells (somatic testing) or cancer and non-cancer cells (paired or concurrent testing).

• Somatic tests cannot confirm or rule out a germline variant. Germline testing is recommended when somatic testing identifies a variant in a hereditary cancer gene.
• Paired somatic-germline tests may report germline variants. This testing analyzes a limited set of hereditary cancer genes and variants and is not a validated germline assay. A negative germline result lowers the likelihood of a germline variant but does not rule it out. A positive germline result should be confirmed with genetic testing for inherited cancer risk.
• Concurrent somatic + germline testing comprises two independent tests. The somatic test assesses a tumor sample for variants associated with targeted treatment options. The germline test assesses a blood sample for variants associated with hereditary cancer risk.

2. Personal and family history

Patients who have a personal or family history suggestive of a hereditary cancer risk should be offered genetic testing for inherited cancer risk, regardless of biomarker test results.

General personal or family medical history suggestive of a genetic predisposition to cancer risk

• Presence of certain cancers
  • Ovarian cancer
  • Pancreatic cancer
  • Triple-negative breast cancer
  • Metastatic breast cancer
  • Male breast cancer
  • Metastatic prostate cancer
  • Medullary thyroid carcinoma
  • Pheochromocytoma or paraganglioma

• Early-onset cancer or adenomatous colon polyps
• Multiple affected relatives with same or associated cancers
• Bilateral or multifocal disease (e.g., renal cell carcinoma or retinoblastoma)
• Multiple cancer diagnoses
• Greater than 10 adenomatous colon polyps
• Disease in the absence of known risk factors, such as lung cancer in a non-smoker
• Ashkenazi Jewish ancestry

See NCCN guidelines for cancer-specific criteria.

3. Microsatellite instability (MSI)

Tumors with high MSI are suspicious for Lynch syndrome. Patients with MSI-high tumors should be offered genetic testing for inherited cancer risk.

4. Variants in hereditary cancer genes

If biomarker testing identifies a pathogenic variant in a gene associated with hereditary cancer, germline testing is typically indicated to rule out a hereditary cancer syndrome.

See Hereditary Cancer Genes for a list.

Some hereditary cancer genes (e.g., TP53, APC, PTEN, STK11) are commonly mutated in cancer cells and may not indicate the need for germline testing after further assessment (2023 ESMO Recommendations).   

There are also some hereditary cancer genes that are more likely to be present in the germline (e.g., BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, and RET) in which genetic testing for inherited cancer risk should be considered (2023 ESMO Recommendations). 

5. Patient factors

Consider patient preferences and motivations for hereditary risk assessment when deciding whether to recommend germline testing. After determining that germline testing is appropriate, the patient should be offered genetic counseling to consider the benefits, risks, and limitations of testing to make the best decision for the individual.

Learn More

Indications for Germline Testing After Genomic Tumor Testing. Interpret genomic tumor test results to determine when a patient should be further evaluated for hereditary (germline) risk.

Interpreting Cancer Biomarker Testing – When is Additional Testing Needed? (CME|CNE). Learn when additional cancer biomarker testing is indicated for further evaluation of genome-informed therapy.

Exploring Cancer Biomarker Testing (CME|CNE). Learn about benefits, limitations, and challenges of using cancer biomarker testing.

Cancer genetic risk assessment. Provides general, breast cancer, and colon cancer specific family history criteria for average, increased, and high risk.

Genetically related cancers. Lists the associated cancers and unique characteristics of common cancer susceptibility genes.

Hereditary Cancer Genes. Lists genes that are associated with hereditary cancer and should be considered for referral when identified on a biomarker test report.

Accessing genetic services tool. Lists tools and websites to help find genetics professionals and provides patient talking points about referring to genetics.

References

Kuzbari Z, Bandlamudi C, Loveday C, et al. Germline-focused analysis of tumour-detected variants in 49,264 cancer patients: ESMO Precision Medicine Working Group recommendations. Ann Oncol. 2023;34(3):215-227. doi:10.1016/j.annonc.2022.12.003  

National Comprehensive Cancer Network (NCCN). NCCN Guidelines for Detection, Prevention and Risk Reduction. (Requires free registration).  

Tung N, Ricker C, Messersmith H, et al. Selection of Germline Genetic Testing Panels in Patients With Cancer: ASCO Guideline. J Clin Oncol. 2024;42(21):2599-2615. doi:10.1200/JCO.24.00662  

Disclaimer
All information in this resource is provided for educational purposes only.