BRCA1 and BRCA2 Flashcards
T or F: most breast/ovarian cancer is caused by heritable mutations
False, most of these cancers arise sporadically
What kind of proteins do the BRCA1 and BRCA2 genes code for?
TUMOR SUPPRESSOR GENES - codes for proteins that are important for responding to DNA damage and maintenance of gene integrity
What is HBOC?
Hereditary Breast and Ovarian Cancer
T or F: patients with HBOC are heterozygous for a mutation in BRCA1 or BRCA2 but NOT BOTH.
True
What chromosomes are BRCA1 and BRCA2 located on?
BRCA1:
Chromosome 17
BRCA2:
Chromosome 13
T or F: women must be homozygous to be affected by BRCA gene mutations
False, heterozygous individuals are affected
**AUTOSOMAL DOMINANT
What is the population risk of breast cancer?
- BRCA1 risk
- BRCA2 risk
Population:
1 in 10
BRCA1:
6 in 10
BRCA2:
4 in 10
**Women heterozygous for BRCA1/2 are at a much elevated risk even over population risk
What is reduced penetrance?
- how does is apply to BRCA1/2
Carrying the BRCA1/2 Allele does not necessarily mean that cancer will develop in that individual.
What is variable expressivity?
- how does it apply to BRCA1/2
- A parent may have a BRCA1/2 mutation, die of BREAST CANCER and pass that mutation to offspring.
- Offspring may die of OVARIAN cancer or some other type related to the BRCA1/2 gene
**Disease will manifest itself in different ways
What are 2 reasons for reduced penetrance in individuals with a BRCA1/2 mutation?
- Disease may just never manifest
2. Typical late onset of breast cancer may mean the individual dies of something else before breast cancer developes
What is the average penetrance of BRCA1/2?
BRCA1 = 6/10 develop cancer BRCA2 = 4/10 develop cancer
Overall penetrance = 50%
What approach is used used to detect mutations in the BRCA1/2 genes?
- why is this necessary?
- Scanning SEQUENCING approach usually paired with an ARRAY
- used because of the large number of mutations on the BRCA1/2 genes
***These mutations are mostly point mutations they why a SEQUENCING approach is most useful
With the large amount of information obtained from the scanning approach, how do you determine if mutations are meaningful or just typical benign polymorphisms?
- Pathogenic Variants have been documented
**Those not known to be benign or pathogenic are given the label of UNCERTAIN SIGNIFICANCE
T or F: mutations to the BRCA1/2 genes often results in loss of function
True
T or F: BRCA1/2 are always sequenced together
True
Where are samples drawn to look for BRCA1/2 mutations?
- DNA type
- what is sequenced
- Blood or Saliva can be used
- GENOMIC DNA (both alleles) is obtained from these samples and sequences
- BRCA1/2 genes from BOTH alleles are sequenced
What are the 3 categories of pathogenicity for mutations in BRCA genes (or any other genes)?
- Pathogenic
- Benign
- Uncertain Significance
What areas of the BRCA genes are targeted when sequencing data?
Regions:
- Promoter
- Coding
- All areas needed for accurate splicing
**Introns are rarely used in analysis
T or F: while point mutations and other small mutations are the predominant mutation forms in the BRCA gene, a significant portion of mutations are large deletions
True, ~15% of all mutations are mutations that span several exons
What is unique about founder populations with regard to:
- Allele Frequency
- Allelic Heterogeneity
Allele Frequency:
- Much HIGHER because small populations inbreed
Allelic Heterogeneity:
- Is REDUCED because the same mutated allele stays in the population rather than having several pathogenic variants
Compare the frequency of BRCA genes in the general population to the Ashkenazi Jew population.
- Prevalence
- Mutation location
General Population:
- Prevalence = 1/500
- Mutations Found in many different spots across different people
Ashkenazi Jews:
- Prevalence = 1/40
- Several common founder mutations
How would your approach to testing an individual in the Ashkenazi Jew population differ from testing the general population?
General Population:
- Scanning Approach due to high amount of Allelic Heterogeneity
Ashkenazi Jew:
- Targeted approach can be used because of Reduced Allelic Heterogeneity
T or F: 90% of mutations occur at one of 3 points on the BRCA1 and BRCA2 genes in the general population
False, this is ONLY true for the Ashkenazi Jew population that has reduced allelic heterogeneity
If a targeted test (for an Ashkenazi Jew) for a mutation in the BRCA gene comes back negative, what is the next step?
- Use a scanning approach
What are 2 strengths of the scanning approach to Genetic Testing for BRCA1/2?
- Its Comprehensive and Powerful method for detecting mutations (in BRCA1/2)
- Gene Panels Provide Options for Expanded Genetic Testing (outside of BRCA1/2)
What are 3 limitations to the scanning approach to Genetic Testing for BRCA1/2?
- Not all mutations will be found
- Some variants are difficult to interpret
- More genes sequenced the greater the possibility of encountering VUS (variants of uncertain significance)
Does having a negative test for a BRCA1/2 test rule out hereditary risk of getting breast cancer?
NO, there are other heritable mutations that are not included in this test
If a patient has a strong family history of breast and ovarian cancer but has a negative result for BRCA1/2 mutations, how would additional genetic testing be done?
- You would run a gene panel of several other genes that could potentially be the cause
***Remember the more tests like this you run, the more likely you are to run into variants of unspecified Significance
How does finding a variant of unspecified significance (VUS) affect your care plan for the patient?
It does NOT have any impact on the care plan, you just go back to treating how you were before the test
A person has a history of breast and ovarian cancer in the family and wants to know her risk of getting the disease, what are the steps in figuring out if its hereditary?
- Test (an) AFFECTED RELATIVE(S) of the consultand
2. Look fore same mutation in the consultand
What can you tell the consultand if her mother tested positive for mutation in a BRCA1/2 gene, but the consultand tested negative for that mutation?
The consultand is then at population risk of getting breast cancer
Suppose the consultand can’t get any of her Affected family members to give a sample for DNA testing but she herself undergoes testing and gets a negative result for mutations, what can you tell the consultand?
Without a sample from relative, you don’t know where to look for the mutation so the result is INCONCLUSIVE
T or F: failure to find pathogenic variants in a patient rules out the hereditary risk of breast cancer?
False
