BRCA

Question 1

Disease mechanism

Answer 1

o Pathogenic mutation in BRCA1/BRCA2 genes TSG (most commonly)
o Transmitted in AD pattern with incomplete penetrance
o Homozygous BRCA2 variants associated with Fanconi Anaemia
BRCA1 colocalises with BRCA2 and RAD51 at sites of DNA damage and activates homologous recombination (Used to repair DS breaks, using sister chromatid as a template. Homologous recombination (HR) maintains genomic integrity by promoting the accurate repair of DSBs through the use of a template strand of DNA (3). For this reason, HR is the primary method of repair during the late S and G2 phases of the cell cycle; when sister chromatids are readily available (4).
o Pathogenic LOF variants can result in inability to perform HR
o Resulting in genomic instability

Question 2

Testing strategy

Answer 2

o All samples should be referred from CGU
o (Except ovarian pilot and Astra Zeneca)
o TSCP
o MLPA
o Sanger (confirm variants / fill gaps in coverage)
o Variant interpretation (BIC database)
o As of October 2017 – all CGU referrals for breast cancer / ovarian cancer tested with EXPAND panel (14 genes)
o Diagnosis (40 day TAT)

Question 3

Benefits of mainstreaming

Answer 3

o Enables patients with high grade serous ovarian cancer (high probability of having BRCA1/2 variant) to be referred for genetic testing directly from their oncologist
o Removes waiting time to be seen by CGU
o Reports are worded differently as oncologists may not have as much genetic knowledge as councellors
o Any positive cases are recommended to be seen by CGU for follow up / familial studies

Question 4

Li Fraumeni

Answer 4

o Rare, AD
o Associated with germline mutations of p53
o Associated with malignancies of breast, brain, adrenal glands

Question 5

Ovarian pilot

Answer 5

o Part of mainstreaming genetics initiative
o Referrals can be accepted by appropriate consultant oncologists
o Reports recommend in positive cases that patients are referred to CGU
o Negative cases- refer to CGU if strong fam history

Question 6

Why do Ash. Jews have higher risk of BC

Answer 6

• Several BRCA1 and BRCA2 founder effects have been identified.
• For example, there are three founder mutations in the Ashkenazi Jewish (AJ) population (see table 2).
• As many as 1 in 40 Ashkenazi Jews are thought to carry one of the three founder mutations.
• Co-existence of more than one founder mutation has been reported in some Ashkenazi families
• Therefore, patients of AJ origin should always be tested for all three AJ mutations
• There are also founder mutations in Polish population (3 common mutations)

Question 7

Describe indirect testing

Answer 7

Indirect testing: Referrals from ‘at risk’ members of a family where no mutation
has been identified and no DNA is available from an affected family member. A
full mutation screen is performed on all the ‘at risk’ family members to try to
identify a BRCA1/2 mutation within the family. Ideally three or more at risk family
members each at 50% risk should be tested. However with recent changes to
NICE recommendations indirect testing is routinely performed on a single individual from a family.

Question 8

What would you mention in a positive report?

Answer 8

• Explain variant present
• Explain the patient is at risk of other BRCA related cancers
• Explain risks to family
• recommend further counselling by CGU

Question 9

Negative BRCA report

Answer 9

• This result shows that the familial pathogenic variant has not contributed to the development of cancer.
• It is likely that she has developed breast/ovarian cancer as a result of factors affecting the general population.
• However, the possibility that she may have an alternative pathogenic BRCA1 or BRCA2 variant or a variant in as yet unidentified genes has not been excluded.
• If you wish to discuss this result please contact the laboratory. These results are dependent upon the information supplied being correct and complete.

Question 10

What are the indicators of a BRCA mutation in the family?

Answer 10

Most commonly diagnosed cancer in the UK
Up to 1 in 5 has a family history
History of ovarian cancer and prostate cancer can be suggestive of germline variant
Manchester / Bodicea scoring system can help identify those patients that are at risk of carrying germline variant and should receive genetic testing

Mutations in BRCA1 or BRCA2 are suspected in an individual with;
• Early onset breast cancer (before 50 years)
• Early onset breast cancer with ovarian cancer at any age
• Bilateral or multifocal breast cancer
• Family history of breast or breast and ovarian cancer with autosomal dominant
transmission
• Personal or family history of male breast cancer
• Ashkenazi Jewish or Polish family history and breast cancer