Hereditary breast cancer genes

We learn about the different hereditary breast cancer genes, with BRCA 1 and BRCA 2 being the most common.

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A small number of women are born with a hereditary predisposition for breast cancer, meaning that their lifetime risk to develop breast cancer is greater than the average of 12% and often they are diagnosed at a younger age. Knowing this information can help with ongoing care and prevention.  

Hereditary breast cancer syndrome (HBC) is a rare genetic condition that impacts about 5-10% of individuals with a diagnosis of cancer. HBC results in a greater risk for breast and other associated cancers and is caused by a mutation in a gene whose normal function is to protect us from cancer.

Are you at risk for HBC?

There are certain features suggestive of risk for HBC for individual’s diagnosed with cancer or in a family’s cancer history, such as:

Individual with cancer only or with a family history

• Breast cancer <40yrs (invasive/DCIS)
• Breast cancer, any age + 1 relative breast cancer <50yrs
• Breast cancer, any age + 1 relative ovarian cancer, any age
• Breast cancers, two primary, one <50yrs 
• Triple-negative breast cancer <60yrs.
• Breast cancer + 2 relatives with breast or related cancer at any age    
• Breast cancer <60yrs and Ashkenazi Jewish
• Epithelial ovarian cancer

Family history

• Diagnosis of breast cancer <50yrs 
• Male breast cancer, any age
• Epithelial ovarian cancer <60yrs
• Combination of two primary cancers  
• Bilateral cancer 
• One relative, both breast and ovarian cancer, any age
• Ashkenazi Jew and breast cancer or ovarian cancer, any age
• Triple-negative breast cancer <60yrs

BRCA1 and BRCA2

The genes most commonly associated with HBC, actually hereditary breast and ovarian cancer syndrome (HBOC), are BRCA1 and BRCA2. The increased risk for cancer is because a person has inherited a mutation in one of their two BRCA1 or BRCA2 genes. 

The prevalence of these mutations is between 1 in 200 and 1 in 1 200 individuals. The impact of these gene mutations on the individual is a greater risk for breast cancer and other associated cancers. This includes breast, ovarian, pancreatic, prostate and melanoma.

Summary of cancer risk (lifetime to age 80 years in %)

CANCER	BRCA1	BRCA2
Breast	60-80%	55-70%
Ovarian	40-58%	15-27%
Contralateral BC risk  (20 years from diagnosis)	30%	15%
Prostate	8,6%	12-15%
Pancreatic	1-3%	2-7%
Male breast cancer	1-2%	2-8%

International professional organisations have established guidelines to reduce the impact of cancer for these individuals known to carry a BRCA1 or BRCA2 mutation through intensive surveillance, focused management and access to preventative options including treatment and prophylactic surgery.

INTERVENTION	DESCRIPTION	CANCER OCCURRENCE RISK REDUCTION
Surveillance	Annual MRI alternated with ultrasound	Earlier detection – Stage 0 and Stage 1
Prophylactic surgery	Bilateral mastectomy	>95%
	Bilateral salpingo-oophorectomy	>90%
Chemoprevention	Tamoxifen	~50%
	Oral contraceptive pill	~56%

The inheritance of a BRCA1 or BRCA2 gene mutation follows a dominant inheritance pattern, meaning that for anyone with a mutation, there is a 50% risk to each of their children to inherit it, regardless of gender, and that it’s most likely that the individual inherited it from one of their parents.

Misconceptions of BRCA1 and BRCA2 mutations

MYTH: Only identified in certain population groups, such as people of Ashkenazi Jewish descent.  

FACT: BRCA1 and BRCA2 mutations have been identified in people of all population and ethnic groups.

MYTH: You can only inherit through maternal or female lineage.

FACT: BRCA1 and BRCA2 mutations are not gender specific. They can be present in both paternal and maternal families, and if a father has a mutation, there remains a 50% chance for this to be passed down to his children, regardless of their gender.

MYTH: BRCA1 and BRCA2 mutations can skip a generation.

FACT: The risk for cancer to occur in a BRCA1 or BRCA2 mutation carrier is never 100%. For this reason, it may look like it skipped a generation but it’s just that the individual with the mutation never developed cancer. Particularly for men, although the risk for prostate and breast cancer is increased, it’s not as high as the increased risk for breast and ovarian cancer in women, and they may not develop cancer.

MYTH: A negative BRCA1 and BRCA2 gene test excludes the likelihood of an HBC.

FACT: For a person with high risk and reported to have tested negative for a BRCA1 and BRCA2 mutation, their risk is not excluded as it may be as a result of another high to moderate risk gene.

OTHER HBC GENES

Since the discovery of the BRCA genes and their role in HBC risk, advances in technology and our ability to interrogate the genome has led to the identification of other genes that confer an increased risk for breast cancer. These genes have been classified into high and moderate risk, based on the increased risk compared to the average. 

These categories are high risk for those with a risk four times expected and moderate for those leading to a two to four times risk. The common genes include:

Hgh risk: BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11 and TP53

Moderate risk: ATM and CHEK2

The table below provides a summary of the cancer risks for these genes and if any are associated with a syndrome, meaning other symptoms present in addition to the risk for cancer.  

High risk	Lifetime risk for breast cancer (by age 70 to 80)	Other cancers*	Syndromes
BRCA1	60-70%	Ovarian
BRCA2	55-70%	Ovarian, prostate, pancreatic
CDH1	40-55%	Stomach
PALB2	35-60%	Pancreas
PTEN	85%	Thyroid, uterine	Cowden syndrome
TP53	54%	Brain, ovarian, GIT, sarcoma, childhood	Li-Fraumeni
STK11	45%	GIT	Peutz-Jeghers
Moderate Risk
ATM	25-40%	Pancreas
CHEK2	27%

*These summarise the more prevalent risks.

Management guidelines and preventative care

As with the BRCA1 and BRCA2 genes, screening guidelines have been established for many of these genes. Access to prophylactic options differ based on the gene involved and current knowledge. Where there is no definitive directive, a multi-disciplinary discussion is recommended, taking into consideration the health of the individual and other factors including family history, personal cancer history, type of cancer and age of diagnosis.

Genetic testing

Genetic testing has recently become more accessible due to the advancements in technology. Genetic tests are affordable, more laboratories are offering the testing, and turn-around time for the result is shorter. This means that most individuals that could benefit from knowing their risk for an HBC will have access. Medical aids are also willing to review the option for testing and fund these tests.

Genetic testing is available through laboratories in SA and overseas. Genetic counsellors are available to assess risk and facilitate the genetic testing process.

Test options include targeted testing for the BRCA1 and BRCA2 genes only, or access to multiple gene panel test, where all HBC genes can be tested simultaneously.  

Benefit of knowing your HBC risk 

• Access intensive screening for early detection.
• Prophylactic surgery and preventative treatment.
• For individuals with a diagnosis of cancer to streamline management based on diagnosis and customise screening accordingly.  
• New treatments have come available that are specifically effective for people with a diagnosis cancer and a mutation in certain HBC genes.
• Alert family members to their risk and enable access for them to reduce their risk.

No family history of cancer, the risk remains high

• A germline mutation in one of the HBC genes identified in about 20% of individuals with a diagnosis of triple-negative breast cancer and many don’t have a family history. The value to such individuals remains high in terms of access to appropriate support and management. 
• Male breast cancer affects about 1 in 1 000 males. About 18% are linked to a genetic mutation in an HBC gene.  

Header image by Adocbe Stock