Histopathology Update: Hereditary Breast Cancer and BRCA Mutations

This special edition of Histopathology Update will focus on BRCA gene testing for hereditary breast and ovarian cancer.
Up to 13% of women with breast cancer will report a positive family history of breast cancer in first degree relatives.
Only 1% however, report MULTIPLE affected relatives which suggests an inherited germline mutation.
Around 25% of familial cancers (3 % of all breast cancers) can be attributed to BRCA1 and BRCA2 gene mutations.

BRCA1 and BRCA2 genes
BRCA1 is located on chromosome 17 and BRCA2 is located on chromosome 13. Both genes encode proteins that act as tumour suppressors mediated via poorly defined transcription regulation, cell-cycle control and degradation pathways. The main function is to halt to the cell cycle in order for DNA repair to occur. A significant mutation in either BRCA1 or BRCA2 genes will result in a non- functional protein that increases the risk of developing a malignancy.

Indications for BRCA1 and BRCA2 gene testing.
There is minimal international variation in the indications for BRCA gene testing with all criteria relying on a patient’s family history. A first degree relative is defined as mother, daughter or sister.
A second degree relative refers to an aunt or grandmother.
One of the following constitutes a positive indication for BRCA1/BRCA2 testing.

For women of non-Ashkenazi Jewish descent:

  • Two first degree relatives diagnosed with breast cancer, one of whom was diagnosed at age 50 or younger.
  • 3 or more first degree or second degree relatives diagnosed with breast cancer regardless of their age at diagnosis.
  • A combination of 1st and 2nd degree relatives diagnosed with breast cancer and ovarian cancer (one cancer type per person).
  • A first degree relative diagnosed with bilateral breast cancer.
  • A combination of 2 or more 1st degree relatives diagnosed with ovarian cancer regardless of age.
  • A 1st or 2nd degree relative diagnosed with both breast and ovarian cancer regardless of age.
  • Breast cancer in a male relative.
  • Patients diagnosed with medullary breast carcinoma.
  • Triple negative breast carcinoma diagnosed before the age of 50 years.

For women of Ashkenazi Jewish descent:

  • Any first degree relative diagnosed with breast or ovarian cancer.
  • 2 second degree relatives on the same side of the family diagnosed with breast or ovarian cancer.

BRCA genes: Location, size and cancer risk associated with mutations

Principles of molecular testing Gene sequencing is undertaken. Given that both genes are extremely long as well the large amount of described mutations, genetic counselling and consultation with the laboratory is required in order to efficiently and cost effectively identify a mutation.
Areas of the genes can be selected based on ethnicity, race or pre-existing known mutation.
Patients of non Ashkenazi Jewish descent, non Afrikaaner descent and no known family mutation can start with investigation of the more commonly mutated areas. Ideally a family member who is affected by cancer is initially
tested; once a mutation is detected then other family members can be screened for the same mutation.

What does a positive BRCA1 and BRCA2 test result mean?
A positive test confers an increased risk of developing cancer (see table). The test provides only an indication of increased cancer risk – and does not tell patients whether they will actually develop cancer or if so, when.
NOT ALL women with a harmful mutation will develop cancer.

Patients will have to be educated on a range of issues including:

  • Difficulties in obtaining medical aid/life insurance cover.
  • Informing family members of the result – giving them a choice to get tested.
  • Implications of disclosure for future relationships and family planning – BRCA1/2 show autosomal dominant transmission which mean that a parent with a mutant gene has a 50% chance of passing on the gene to their off-spring.
  • Risk reduction strategies vary and include increased surveillance/screening, medical (anti oestrogen therapy) and surgical interventions (mastectomy, oophorectomy).


  • BRCA mutation related breast cancer is rare and constitutes 3% of all breast cancers.
  • Selection of patients suitable for testing relies on family history.
  • Test interpretation is complicated in some instances by the large size of the BRCA gene and the large number of documented mutations.
  • Patients must undergo complete genetic counselling which will help them establish their cancer risk profile, suitability for testing and possible implications of the test results.

Genetic counselling is the first step. Patients with adverse family history should undergo genetic counselling prior to undertaking this test.

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