Germline Genetic Testing for Cancer

Patient Guideline

Publication Date: May 17, 2024
Last Updated: June 10, 2024

Objective

Objective

  • This patient summary is about the key takeaways from the American Society of Clinical Oncology (ASCO) guideline for the selection of germline genetic testing panels in patients with cancer.
  • The purpose of this patient summary is to provide new evidence-based recommendations to guide adult patients with cancer and caregivers in making informed decisions about their treatment plans.

Overview

Overview

  • Genetic testing looks for genetic mutations (a harmful change in the genetic material). It can be somatic or germline.
    • Somatic testing (also known as tumor genomic profiling, or tumor testing) uses a tumor sample. It is limited to mutations in the tumor that first appear in the person tested rather than in a previous generation.
    • Germline testing identifies mutations passed down from one generation to the next in families with inherited cancer or heightened cancer risk.
  • This testing has two main functions:
    • It can predict future cancer risks for patients and their relatives.
    • It helps the cancer care team when deciding on the best treatment.
  • Genetic testing can be:
    • A multi-gene panel: This allows for finding mutations in many genes at one time. Because many different genes can cause the same or related cancers, this type of testing is often recommended.
    • Single gene testing: This may be recommended if a family member had genetic testing that identified a specific mutation.
  • Cancer can be:
    • Primary cancer: This is the original site where cancer begins in the body.
    • Secondary or metastatic cancer: Cancer that has spread to other parts of the body.

Family History

Family History

The cancer care team may ask you the following questions:

  • Do you know of any cancers in first-degree biological relatives (siblings, parents, or children)?
  • Do you know of any cancers in second-degree biological relatives (grandparents, aunts, uncles, grandchildren, nieces, nephews, half-siblings)?
  • Do you know of any cancers in the third-degree biological relatives (cousins)?
    • Only if it is important, the cancer care team will ask about the third-degree relatives.
  • If there is cancer in the family: What types of primary cancer were there, and what is the age at cancer diagnosis for each one? Were more than one cancer of a single type involved (for example breast cancer in both breasts)?
  • Do you know of any relative who has had germline genetic testing, and if so, what were the results?
  • What is your ethnicity?

Germline multi-gene panel testing

  • Multi-gene panel testing will be offered if more than one gene is relevant.
  • The basic panel will include the most important genes related to each patient’s personal and family history of cancer. It might also include other less important genes.
  • A larger panel that looks at more genes can be ordered if it is clear that this will provide useful information.
  • Sometimes, a smaller panel is done first if quick results are needed for making treatment decisions. Later, the test can be expanded to look at more genes if needed.

Genes to be included in multi-gene panels

If germline multi-gene panel testing is offered, testing for mutations in the genes in Table 1 is recommended for the indicated populations of patients with cancer.
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Each mutation is assigned a specific name using letters/numbers as abbreviations to make it easier for healthcare providers and scientists to talk about them. You do not need to know the full names of the mutations, but it is important to find out if you have any of them.
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TABLE 1. Genes Recommended for Testing and Inclusion in Multi-Gene Panels for Selected Cancers

Having trouble viewing table?
Cancer Type and Specific Population More Important Less Important
Breast Cancer BRCA1, BRCA2, PALB2

CDH1, PTEN, STK11, TP53		 ATM, BARD1, CHEK2, RAD51C, RAD51D

NF1
Colorectal Cancer APC, EPCAM, MLH1, MSH2, MSH6, MUTYH, NTHL1, PMS2, POLD1, POLE

BMPR1A, SMAD4, STK11, TP53		 AXIN2, CHEK2, MBD4

GREM1, MSH3, PTEN, RNF43
Endometrial Cancer EPCAM, MLH1, MSH2, MSH6, PMS2

PTEN, STK11		 N/A
Gastric Cancer APC, CTNNA1, EPCAM, MLH1, MSH2, MSH6, PMS2

BMPR1A, CDH1, SMAD4 , STK11		 N/A
Gastrointestinal Stromal Tumors (GISTs) KIT, PDGFRA

If SDH-deficient or SDH-mutant tumor: SDHA, SDHAF2, SDHB, SDHC, SDHD

If NF1-mutated tumor: NF1		 If tumor is not SDH-deficient, SDH-mutated, or NF1-mutated: NF1, SDHA, SDHAF2, SDHB, SDHC, SDHD
Medullary Thyroid Carcinoma RET N/A
Non-Small Cell Lung Cancer – if EGFR tumor pathogenic variant (such as p.T790M) found with no prior EGFR-TKI therapy EGFR

STK11		 TP53
Adrenocortical Tumors APC, EPCAM, MEN1, MLH1, MSH2, MSH6, PMS2, TP53 N/A
Cutaneous Melanoma CDKN2A, CDK4 BAP1, MC1R, MITF, POT1, TERT

PTEN
Uveal Melanoma BAP1 N/A
Ovarian Cancer (Epithelial) BRCA1, BRCA2, BRIP1, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, RAD51C, RAD51D ATM
Pancreatic Adenocarcinoma ATM, BRCA1, BRCA2, CDK4, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2

STK11 TP53		 APC
Phaeochromocytomas and Paragangliomas (PPGLs) FH, MAX, RET, SDHA, SDHB, SDHC, SDHD, TMEM127

NF1, VHL		 EGLN1, EPAS1, KIF1B, MET, SDHAF2
Prostate Cancer BRCA1, BRCA2, EPCAM, HOXB13, MLH1, MSH2, MSH6, PMS2 ATM, CHEK2, PALB2
Renal Cell Carcinoma BAP1, FH, FLCN, MET, SDHA, SDHAF2, SDHB, SDHC, SDHD

PTEN, VHL		 TSC1, TSC2
Sarcoma (soft-tissue or osteosarcoma) TP53 NF1, RB1
NOTE: Given the importance and prevalence of BRCA1, BRCA2, and the Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM) it is reasonable to include these genes in multi-gene panels for any patient with cancer undergoing germline genetic testing.
Adapted from: Selection of germline genetic testing panels in patients with cancer: ASCO guideline.

Germline versus somatic genetic testing

​​​​​​Even if somatic testing results are negative, germline testing still needs to be done for those that meet testing criteria.
  • A large number of germline mutations can be missed in somatic testing.
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Regardless of germline genetic testing criteria, when an important somatic mutation is found, germline genetic testing should be offered.

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Additional resources

Additional resources

Source Citation

Tung N, Ricker C, Messersmith H, et al. Selection of Germline Genetic Testing Panels in Patients with Cancer: ASCO Guideline. J Clin Oncol. 2024 May 17. doi: JCO.24.00662