BRCA1/2 Testing 

Interpreting a BRCA1/2 Gene Test Result: 
There are 3 possible outcomes following testing: 
1. Positive – Mutation has been confirmed 
2. Negative –(‘true negative’) the known mutation identified in a relative has not been identified or no variant is found in either gene 
3. Variants of Uncertain Clinical Significance (VUS) – ~4-5% of BRCA1/2 testing may result in VUS, further reduced in well-characterised ethnic populations. 
Agreed standards for reporting and classifying sequence variants are clinically well accepted. It remains best practice to ensure that both a positive and VUS result prompts a referral to the genetics services. 
 
BRCA1 
The BRCA1 gene (Chromosome 17) is involved in DNA repair. There is a founder mutations amongst the Ashkenazi Jewish and eastern European populations. Approximately 1 in 500-900 women will have a mutation in the BRCA1 gene. Specific ethnic groups like Ashkenazi Jews will have a higher incidence of a mutation in BRCA 1 – in this group it is around 1 in 40 women. 
Having a BRCA1 mutation confers lifetime breast cancer risks of approximately 60-85% and 40-60% for developing ovarian cancer. Approximately 70% of BRCA1 related breast cancers are called “Triple Negative” Breast Cancers (ER negative, PR negative and HER2 negative). 
 
BRCA2 
This is a DNA repair gene (Chromosome 13). The lifetime breast cancer risk has a wider range (40-85%) compared to BRCA1, and lower risks of ovarian cancer (15-30%). Approximately 10% of Male breast cancer is associated with BRCA2 mutation, a trend not seen in BRCA1 carriers. 
 
PALB2 – Stands for the Partner and Localiser of BRCA2. It confers lifetime risks of breast cancer of around 40-50% and is associated with pancreatic cancer and Fanconi’s anaemia. 
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