Indications for germline testing in cancer patients
Recent studies have found that 12-17% of cancer patients carry pathogenic germline variants in cancer predisposition genes. Determining when germline testing after genomic tumor testing is warranted requires assessing information from the test report as well as patient factors.
This resource lists the general risk factors and indications for germline testing that should be considered for cancer patients. See cancer-specific guidelines for more detail about germline testing criteria.
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 tumor test: tumor cells (somatic) or tumor and normal 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 of interest.
- Paired somatic/germline tests may or may not report germline variants. Look at the test parameters to determine if the germline testing performed was sufficient or whether further evaluation is necessary.
- Concurrent somatic + germline tests provide both a somatic report for genome-informed treatment as well as a comprehensive hereditary cancer panel.
2. Personal and family history
Patients who have a personal or family history suggestive of a hereditary cancer syndrome should be offered germline genetic testing, regardless of genomic tumor test results.
General personal or family medical history suggestive of a higher than average genetic contribution to cancer risk
- Presence of certain cancers
- Ovarian cancer
- Pancreatic cancer
- Triple-negative 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 primaries
- Greater than 10 adenomatous colon polyps
- Disease in the absence of known risk factors, such as lung cancer in a non-smoker
- Ethnic predisposition
See NCCN guidelines for cancer-specific criteria.
3. Microsatellite instability (MSI)
Tumors with MSI are suspicious for Lynch syndrome. Patients with MSI-high tumors should be offered germline testing.
4. Cancer susceptibility gene
If genomic tumor testing identifies a pathogenic variant in a gene associated with cancer susceptibility, germline testing is typically indicated to rule out a hereditary syndrome.
See Cancer Susceptibility Genes for a list.
5. Clinical significance of the specific variant
Pathogenic or likely pathogenic variants in cancer susceptibility genes are a concern for hereditary cancer risk.
6. 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 in order to make the best decision for the individual.
For more information
- 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.
- Cancer susceptibility genes. This resource lists genes that are associated with hereditary cancer and should be considered for referral when identified on a genomic tumor test report.
- Accessing genetic services tool. Lists tools and websites to help find genetics professionals and provides patient talking points about referring to genetics.
Cobain EF, Jacobs M, Wu Y, et al. Tumor/normal genomic profiling in patients with metastatic solid tumors identifies pathogenic germline variants of therapeutic importance. J of Clin Oncol. 2020 May; 38(15_suppl):1501-1501 .
DeLeonardis K, Hogan L, Cannistra SA, Rangachari D, Tung N. When Should Tumor Genomic Profiling Prompt Consideration of Germline Testing? J Oncol Pract. 2019 Sep;15(9):465-473.
Lincoln SE, Nussbaum RL, Kurian AW, et al. Yield and Utility of Germline Testing Following Tumor Sequencing in Patients With Cancer. JAMA
Mandelker D, Donoghue M, Talukdar S, et al. Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group. Ann Oncol. 2019;30(8):1221-1231.
Meric-Bernstam F, Brusco L, Daniels M, Wathoo C, et al. Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol. Ann Oncol. 2016 May;27(5):795-800.
Miller DT, Lee K, Chung WK et al. ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23(8):1381-1390.
National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (version 1.2021). Published September 8, 2020. Accessed 11/5/20.
National Comprehensive Cancer Network. Genetic/familial high-risk assessment: colorectal (version 1.2020). Published July 21, 2020. Accessed 11/5/20.
Samadder NJ, Riegert-Johnson D, Boardman L, et al. Comparison of Universal Genetic Testing vs Guideline-Directed Targeted Testing for Patients With Hereditary Cancer Syndrome. JAMA Oncol. 2020 Oct 30.
Stadler ZK, Maio A, Kemel Y, et al. 2020 Targeted therapy based on germline analysis of tumor-normal sequencing (MSK-IMPACT) in a pan-cancer population. Journal of Clinical Oncology. 2020 May; 38(15_suppl):1500-1500.
This resource was developed as part of Precision Oncology Online Education and the Maine Cancer Genomics Initiative (MCGI) and is supported by The Harold Alfond Foundation, Maine Cancer Foundation and The Jackson Laboratory.
Updated October 2021
All information in Precision Oncology Online Education is provided for educational purposes only. This information is not a substitute for clinical guidance or the consultation of a medical professional. Always seek the advice of a qualified health professional with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read in Precision Oncology Online Education. Reliance on any information in Precision Oncology Online Education is solely at your own risk. The Jackson Laboratory does not endorse or recommend any specific procedures, tests, products, services, health professionals or other information that may be found in Precision Oncology Online Education.