Genetics and Hereditary Cancers

Hereditary Breast Cancer: Guide for Health Pros

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Breast cancer is the second most commonly diagnosed cancer in women (only skin cancer is more common), but the death rates for breast cancer have steadily decreased in women in recent years. This decrease is attributable, in part, to improvements in both early detection and treatment.

The genetic risk assessment service at UT Southwestern Simmons Comprehensive Cancer Center offers testing and genetic counseling for breast cancer and all other identified cancers. Based on your personal and family history of cancer, our genetic counselors can identify your level of risk, determine if genetic testing is appropriate, and provide guidance for an early detection and prevention strategy.

Watch a video about hereditary breast cancer management.

Breast Cancer Facts

One in 8 women (12 percent) will develop breast cancer in her lifetime. Of all breast cancer cases, only about 5 to 10 percent are hereditary, linked to gene mutations inherited from one’s mother or father.

Multiple genes are associated with hereditary breast cancer, but mutations in BRCA1and BRCA2 genes are the most common cause of the hereditary form of the disease. Prediction models can estimate an individual’s risk for BRCA1 or BRCA2 mutations. Additional information on breast cancer predisposition genes can be found on the Hereditary Breast Cancer Gene List below.

Approximately 15 to 20 percent of breast cancer is familial, meaning the disease occurs more often in family members than can be expected in the general population even though a particular gene mutation has not been identified in the family. With familial breast cancer, the specific cause of breast cancer is unknown but is likely due to combinations of risk factors, including genetics, lifestyle, and environment that increase risk in the family.

Screening recommendations vary for women with an increased lifetime risk for breast cancer based on a hereditary cancer syndrome or family history.

The remainder of breast cancer diagnoses (around 70 percent) is considered random or sporadic and non-hereditary, without a known etiology. Risk factors for sporadic breast cancer include:

  • Age
  • Early-onset menses/late menopause
  • Hormone exposure
  • Late or no pregnancies
  • Diets high in fat/no physical activity
  • Having “dense” breasts
  • Benign breast disease (ADH/ALH)
  • Alcohol
  • BMI/body type


Cowden Syndrome


Component Cancers
Breast, uterine, thyroid, colon, and renal cancers

Of Note
Associated with macrocephaly; colon polyps (hamartomatous); skin finding such as acral keratosis, facial trichilemmomas, and oral papillomatous papules; autism; lipomas; fibrocystic breast disease; thyroid nodules; and uterine fibroids.

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Hereditary Breast and Ovarian Cancer Syndrome


Component Cancers
Breast, ovarian, prostate, male breast, pancreatic, melanoma, and possibly colon cancers

Of Note
There are three common founder mutations in the Ashkenazi Jewish population.

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Hereditary Diffuse Gastric Cancer


Component Cancers
Diffuse gastric cancer and lobular breast cancer

Of Note
Gastric cancer incidence varies widely by geographic regions. Patient’s origin should be considered when evaluating CDH1 criteria.

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Li-Fraumeni Syndrome


Component Cancers
Early-onset breast cancer, sarcomas, brain tumors, leukemia, lymphoma, and adrenal cortical carcinoma

Of Note
Individuals with LFS have a 50 percent risk for cancer by age 30 and 90 percent by age 60. They often have multiple tumors. Individuals are radiation sensitive – radiation therapy poses a risk for causing subsequent tumors and should be avoided when possible.

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Moderate Risk Breast Cancer Genes


Component Cancers

  • ATM*: Breast, pancreatic, and possibly ovarian, prostate, melanoma, endometrial, head and neck, and hematologic cancers
  • CHEK2: Breast, colon, prostate and possibly ovarian, thyroid, and renal cancers
  • PALB2*: Breast, pancreatic, and possibly ovarian

* These risks are associated with heterozygous mutations.

Of Note

  • ATM: Individuals with two separate (homozygous) ATM mutations have a syndrome known as ataxia telangiectasia.
  • CHEK2: 1100delC mutation is the most common CHEK2 mutation in Northern European populations.
  • PALB2: PALB2 works in the same biochemical pathway as BRCA2. Magnitude of breast cancer risk is linked to family history: lifetime risk of breast cancer increases with number of close relatives diagnosed with breast cancer at a young age.

Download Fact Sheets
CHEK2 Fact Sheet - English

PALB2 Fact Sheet - English

Neurofibromatosis Type 1


Component Cancers
Breast cancer, gliomas, malignant peripheral nerve sheath tumors, pheochromocytoma, leukemia, GIST, and rhabdomyosarcoma

Of Note
Clinical diagnosis is typically made during childhood based on classic noncancerous findings, including neurofibromas, café au lait macules, axial/inguinal freckling, Lisch nodules, bone

Peutz-Jeghers Syndrome


Component Cancers
Small bowel, colon, stomach, pancreatic, breast, cervical, ovarian sex cord tumors (SCTATs), and sertoli cell tumors

Of Note
Classic pigmentation of lips and buccal mucosa, typically seen PJ-type hamartomatous polyps.

Management of High-Risk Women

The American Cancer Society recommends high-risk surveillance for women with a calculated lifetime breast cancer risk that is greater than 20 percent.

The lifetime risk estimation is based on family history (using tools such as the Claus model).

High-risk surveillance includes alternating annual breast MRI and mammogram to ensure breast cancer screening every 6 months.

The National Comprehensive Cancer Network (NCCN) has established and published guidelines for cancer care, which are focused on quality, effectiveness, and efficiency. The guidelines are continuously updated to reflect current research. Specific recommendations for screening and management of individuals with an increased lifetime risk of cancer due to a hereditary cancer syndrome are briefly summarized below. Please note that most current and detailed guidelines are available through NCCN “Genetic/Familial High-Risk Assessment: Breast and Ovarian.”

NCCN Recommendations for Breast Cancer Risk Management: High-Risk Genes


NCCN recommendations for high-risk breast cancer genes, including BRCA1, BRCA2, CDH1, PTEN, STK11, and TP53 have been established. Current guidelines (version 1.2015) recommend breast cancer screening beginning between ages 20 and 30 depending on gene and youngest age of breast cancer diagnosis in the family. Screening involves alternating breast MRI and mammography every six months. Mammograms are not typically recommended for women younger than age 30 and at-risk individuals should discuss available screening options with their physicians. Individuals may also consider risk-reducing mastectomy due to the high lifetime risk of breast cancer. This surgery is done prophylactically, meaning prior to cancer diagnosis as a preventable measure.

NCCN Recommendations for Breast Cancer Risk Management: Moderate-Risk Genes


NCCN recently published recommendations for moderate-risk genes (version 1.2015). Annual breast MRI as part of routine breast cancer screening is recommended for individuals with a mutation in ATM, CHEK2, and PALB2 genes due to the >20 percent lifetime risk of breast cancer. Age to begin screening is not specified and may be based on personal risk factors and family history. For example, breast cancer screening in the general population is recommended 10 years prior to the youngest age of diagnosis in the family or at age 40. Women at an increased risk should discuss this information with their physicians to establish an appropriate screening routine.

Prediction Models for Breast Cancer Risk

At Simmons Comprehensive Cancer Center, we use a variety of assessment tools designed to predict an individual’s lifetime risk of developing breast cancer. Not all tools can be appropriately applied to all patients. Each tool is most effective when the patient’s characteristics and family history are similar to those of the study population on which the tool was based. Two such tools available at Simmons Cancer Center, which are widely used in research studies and clinical counseling, are known as the Gail model and the Claus model. Both have limitations, and the risk estimates derived from the two tools may differ for an individual patient.

The Gail Model

Designed by researchers at the National Cancer Institute and the National Surgical Adjuvant Breast and Bowel Project, the Gail model is primarily focused on personal risk factors for breast cancer and estimates the patient’s five-year and lifetime risk of breast cancer. The five-year risk can be used for chemoprevention recommendations if the risk is greater than 1.67 percent. The Gail model considers the following factors:

  • Patient’s age (for individuals 35 and older)
  • Age at which patient has her first menstrual period
  • Age at which patient delivers her first live birth
  • Patient’s number of biopsies
  • Patient’s history of atypical hyperplasia
  • The number of first-degree female relatives with breast cancer

The main limitation of the Gail model is that it includes only first-degree relatives, which underestimates the risk in women with breast cancer history in their paternal lineage. The Gail model also does not consider the age of onset of breast cancer.

The Claus Model

With the Claus model, lifetime breast cancer risk estimates are based on family history. Unlike the Gail model, the Claus model considers the number and ages of onset of breast cancer in first- and second-degree relatives. It also distinguishes between maternal and paternal relatives.

If the lifetime risk is greater than 20 percent using the Claus model, the patient qualifies for high-risk surveillance, according to the American Cancer Society.

Among the limitations of the Claus model are that it applies only to women with a family history of breast cancer and does not consider nonhereditary risk factors. In addition, the Claus model can calculate risk for only up to two relatives with breast cancer.

Other Risk Assessment Tools

Models for assessing an individual’s lifetime risk for developing breast cancer and likelihood of having BRCA1 and BRCA2 mutations are also available at Simmons Cancer Center.

A tool called BRCAPro, for example, considers a patient's age, the age of first- and second-degree relatives and their breast and ovarian cancer status, along with BRCA1 and BRCA2 mutation frequencies and cancer penetrance. The patient’s ethnicity and age at which she has had a salpingo-oophorectomy (the removal of the ovaries and Fallopian tubes) are also components of the BRCAPRO risk calculation. This model does not consider nonhereditary risk factors.

Another tool, called the Cuzick-Tyrer model, considers the patient's age; BMI; age at first menstrual period; age at first live birth; age at menopause; hormone replacement therapy use; breast biopsies; atypical ductal hyperplasia; lobular carcinoma in situ; and family history of breast and ovarian cancer in first- and second-degree relatives. This model also estimates the risk for the presence of a non-BRCA1/BRCA2 breast cancer susceptibility gene mutation.