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. The challenge is identifying which patients are most appropriate for germline testing.

The patient’s personal history, family history, type of cancer and results from genomic tumor testing can help to guide decision making around which patients should have further work-up and/or be offered germline testing. Cancer-specific clinical guidelines and recommendations often identify the criteria for germline testing.

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.  

Personal and family history red flags

The following are features of the personal or family medical history that may suggest a higher than average genetic contribution to cancer risk.

  • Presence of certain cancers (e.g., ovarian, pancreatic, triple negative breast cancer ≤ 60, male breast cancer, metastatic prostate)
  • 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
  • Ethnic predisposition

Results from genomic tumor testing

Genomic tumor testing (GTT) is used to identify genomic variants that can inform diagnosis, prognosis, and treatment. Certain findings occur more often in individuals carrying germline variants.

Results that should prompt additional genetic work-up and/or germline testing.

  • Pathogenic variants in BRCA1 or BRCA2, regardless of cancer type
  • Pathogenic variants in a mismatch repair gene (e.g., MSH2, MLH1, PMS2, MSH6, EPCAM) should be confirmed with germline testing
  • High level of microsatellite instability (MSI-H)
  • Pathogenic variant in a gene known to be associated with hereditary cancer, which is not commonly somatically mutated (e.g., CHEK2, BRCA1, BRCA2, PALB2, MSH2, and MSH6). In general, the less frequent the gene is known to have somatic variants in the given cancer, the more likely germline testing should be pursued.
  • Founder mutations, which are mutations common in individuals of certain ancestry (e.g., BRCA1 185delAG in individuals with Ashkenazi Jewish ancestry)
  • Same pathogenic variant detected in multiple primary cancers
  • Hypermutated and microsatellite stable (MSI-L) cancers in patients with multiple colorectal adenomas and/or colorectal and endometrial cancers

Results that may indicate there is NOT a hereditary component

  • Pathogenic variant in a gene known to be associated with hereditary cancer that frequently has somatic mutations (e.g., TP53, APC, PTEN)
  • Hypermutated and microsatellite stable in cancer types other than colorectal and endometrial
  • In tumor-only testing, variant allele frequency should not be used to make decisions about whether a variant is present in the germline

Regardless of results on genomic tumor testing, individuals who meet clinical criteria for germline testing should be offered genetic counseling and germline testing. Only germline testing can definitively determine the presence or absence of a germline variant.


For more information


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 Netw Open. 2020;3(10).

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.

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 the Maine Cancer Genomics Initiative (MCGI) and is supported by The Harold Alfond Foundation, Maine Cancer Foundation and The Jackson Laboratory. 

December 2020