Cancer Genetic Risk Assessment

Categorizing Risk

The purpose of genetic risk assessment is to identify individuals at elevated cancer risk who may benefit from genetic testing, additional screening or preventive interventions. Using clues from the personal and family history, you can classify an individual as average (general population), increased (moderate), or high (strong) risk.

General Criteria for Average, Increased (Moderate) and High (Strong) Cancer Risk

Average Risk for Cancer

An absence of the red flags and risk factors associated with increased or high risk.

Increased (Moderate) Risk for Cancer

A patient may be at increased risk for cancer because of a family history contribution, personal or lifestyle risk factors, or a combination of the two. Family histories suggestive of increased risk may show familial clustering of cancer but do not meet the criteria for high risk.

Family history: 

  • One first-degree relative with common cancer at average age only
  • One first- and one second-degree relative or two second-degree relatives with common cancer at average ages only

In addition to family history, personal history risk factors can increase an individual's risk of developing cancer. Consider the following risk factors:

  • Medical history
  • Patient race or ethnicity
  • Reproductive history
  • Lifestyle, behaviors, and exposures
High (Strong) Risk for Hereditary Cancer

Individuals at high risk for a hereditary cancer syndrome typically have one or more of these family history features:

  • 3 or more relatives with similar or related cancers
  • 2 generations of cancer cases, and
  • At least 1 individual diagnosed at a younger than usual age
  • Known hereditary cancer mutation or clinical diagnosis
  • Presence of certain cancers in patient or close blood relatives (e.g., ovarian, pancreatic, triple negative breast, multiple primary breast, male breast, metastatic or high/very high grade prostate)
  • Other characteristic features may include:
    • At least 1 individual with bilateral or multiple primary tumors
    • At least 1 relative with a rare tumor or rare presentation, or a pathology associated with hereditary cancer
    • Presence of other nonmalignant features
    • Absence of environmental risk factors
 

Breast Cancer Genetic Risk Stratification

Risk Level

Personal and Family History Evidence

Average
  • No first- or second-degree relatives^ with breast or ovarian cancer; OR
  • More distant relatives with a breast cancer diagnosis or diagnoses after age 50

Increased (moderate)
  • Prior history of breast cancer, lobular neoplasia (LCIS/ALH), or atypical ductal hyperlasia
  • 5-year risk ≥ 1.7% in women ≥ 35 years using the Gail model, or ≥ 20% lifetime risk defined by risk models
  • Thoracic radiotherapy < 30 years

High (strong)
  • Known pathogenic variant (mutation) in the family
  • Somatic tumor testing suggesting a hereditary cancer syndrome
  • Patient or first-degree relative diagnosed with exocrine pancreatic cancer
  • Diagnosis in patient, or first- or second-degree relative with
    • breast cancer (at age 45 or younger)
    • triple negative breast cancer
    • multiple primary breast cancers
    • ovarian, certain prostate cancers, or male breast cancer at any age
    • breast cancer or prostate cancer diagnosis at any age and Ashkenazi Jewish ancestry
  • Two or more first, second, or third degree relatives on same side of family with breast or prostate cancer^
  • Three or more total diagnoses of breast cancer in patient, first, second, or third degree relatives on the same side of the family
^ First degree relatives are parents, children, and siblings. Second degree relatives are grandparents, grandchildren, uncles and aunts. Third degree relatives are cousins, great-grandparents, great uncles and great aunts.

 

Please see NCCN Genetic/Familial High Risk Assessment: Breast, Ovarian and Pancreatic: Hereditary Testing Criteria and Breast Cancer Screening and Diagnosis for more detailed criteria, including family history presentation for rare syndromes.

In addition to family history, personal history risk factors can increase an individual’s risk of developing cancer. For example, a medical condition such as breast atypia may increase breast cancer risk. Behavioral or lifestyle choices (e.g., cigarette use, alcohol consumption) can affect cancer risk generally; reproductive history can affect a woman’s breast cancer risk (e.g., age at menarche).

Colorectal Cancer Genetic Risk Stratification

Risk Level

Personal and Family History Evidence

Average
  • No relatives with CRC or advanced adenomatous or sessile serrated colon polyps

Increased (moderate)
  • Personal history of CRC, IBD, cystic fibrosis, advanced adenoma or sessile serrated polyp
  • One or more first-degree relatives with CRC, or advanced adenoma or sessile serrated polyp (>1cm) at any age
  • Second or third degree relative with CRC at any age

High (strong)
  • Known pathogenic variant (mutation) in the family
  • Somatic tumor testing suggesting a hereditary cancer syndrome
  • Personal history of CRC with dMMR* or MSI-High histology
  • CRC or endometrial cancer in patient, or first- or second-degree relatives AND, generally:
    • Diagnosis < 50 years
    • Two or more primary LS-associated cancers**
    • Two or more affected first- or second-degree relatives 
  • One or more first- or second-degree relatives on the same side of the family diagnosed with LS-associated cancer < 50 years, or with two primary LS-associated cancers
  • Two or more first- or second-degree relatives on the same side of the family with LS-associated cancer, one diagnosed < 50 years
  • Three or more first- or second-degree relatives on same side of family with LS-associated cancer at any age
  • ≥ 5% risk of a LS gene mutation based on predictive models (i.e., PREMM5)+
   
^ First degree relatives are parents, children, and siblings. Second degree relatives are grandparents, grandchildren, uncles and aunts. Third degree relatives are cousins, great-grandparents, great uncles and great aunts.
* Deficient mismatch repair (dMMR) is determined through immunohistochemistry (IHC) staining of tumor samples for presence or absence of protein products of the Lynch syndrome genes responsible for mismatch repair. Testing may use either IHC or microsatellite instability analysis (MSI).
** Lynch syndrome-related cancers include colorectal, endometrial, gastric, ovarian,  pancreas, urothelial, biliary tract, small bowel, brain (usually glioblastoma), as well as sebaceous skin lesions and keratoacanthomas.
+ NCCN notes that  ≥ 2.5% risk of a LS gene mutation may be used.

 

Please see NCCN Genetic/Familial High Risk Assessment: Colorectal Assessment for Hereditary CRC Syndromes and Colorectal Cancer Screening for more detailed criteria. 

In addition to family history, personal history risk factors can increase an individual’s risk of developing cancer. For example, behavioral or lifestyle choices (e.g., cigarette use, alcohol consumption) can affect cancer risk generally; diet and inflammatory bowel disease can increase the risk of CRC.

Cancer Genetic Risk Assessment Models

Risk assessment tools and models can help identify patients at increased risk. Different models may provide slightly different risk numbers, depending on the factors considered in the algorithm.

In addition to the models and risk calculators listed below, providers can also look to the literature for empiric risk estimates. This can be particularly helpful when assessing risk levels for a family that demonstrates increased risk based on clustering of cancer.

Cancer Genetic Red Flags Checklist. This tool includes a general list of red flags as well as breast and colon specific red flags.

 

Breast Cancer Risk Assessment Tools

Breast Cancer Risk Assessment Tool (National Cancer Institute). Considers personal history, reproductive history, and some family history to provide 5-year and lifetime risk estimates for breast cancer.

Breast Cancer Genetics Referral Screening Tool (Georgia Department of Public Health). Collects targeted family history information about breast and ovarian cancer. Screens for the appropriateness of a referral to cancer genetic services based on risk level. Includes a patient version.

NCCN Criteria for Further Genetic Risk Evaluation: Guidelines for Detection, Prevention and Risk Reduction of Breast/Ovarian and Colorectal Cancer.  Includes personal and family history features that should warrant consideration of a referral to cancer genetic services. Requires free account setup.

Tyrer-Cuzick Risk Assessment Tool (IBIS). Collects targeted personal and family history information and estimated 10-year and lifetime risk of breast cancer, as well as risk of HBOC.

For Patients

Family HealthLink (Ohio State University Medical Center). Collects personal and family history information to determine a risk estimate for cancer and cardiovascular disease.

Colon Cancer Risk Assessment Tools

Colon Cancer Risk Assessment Tool (National Cancer Institute). Considers personal history, diet, exercise, exposures, and some family history to provide 5-year, 10-year and lifetime risk estimates for colon cancer.

PREMM model. A clinical prediction algorithm that estimates the probability of an individual carrying a germline mutation for Lynch syndrome.

For Patients

Colon Cancer Risk Assessment Tool (Cleveland Clinic).Collects personal, behavioral, and family history information to determine a risk estimate for colorectal cancer.

3 Questions to Assess Your Familial Colorectal Cancer Risks (Columbia University). Asks three basic questions to determine if an individual is at increased risk.

 

Updated August 2023

 

 

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