BRCA1 and BRCA2

Question 1

T or F: most breast/ovarian cancer is caused by heritable mutations

Answer 1

False, most of these cancers arise sporadically

Question 2

What kind of proteins do the BRCA1 and BRCA2 genes code for?

Answer 2

TUMOR SUPPRESSOR GENES - codes for proteins that are important for responding to DNA damage and maintenance of gene integrity

Question 3

What is HBOC?

Answer 3

Hereditary Breast and Ovarian Cancer

Question 4

T or F: patients with HBOC are heterozygous for a mutation in BRCA1 or BRCA2 but NOT BOTH.

Answer 4

True

Question 5

What chromosomes are BRCA1 and BRCA2 located on?

Answer 5

BRCA1:
Chromosome 17

BRCA2:
Chromosome 13

Question 6

T or F: women must be homozygous to be affected by BRCA gene mutations

Answer 6

False, heterozygous individuals are affected

**AUTOSOMAL DOMINANT

Question 7

What is the population risk of breast cancer?

• BRCA1 risk
• BRCA2 risk

Answer 7

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

Question 8

What is reduced penetrance?

- how does is apply to BRCA1/2

Answer 8

Carrying the BRCA1/2 Allele does not necessarily mean that cancer will develop in that individual.

Question 9

What is variable expressivity?

- how does it apply to BRCA1/2

Answer 9

• 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

Question 10

What are 2 reasons for reduced penetrance in individuals with a BRCA1/2 mutation?

Answer 10

1. Disease may just never manifest

2. Typical late onset of breast cancer may mean the individual dies of something else before breast cancer developes

Question 11

What is the average penetrance of BRCA1/2?

Answer 11

BRCA1 = 6/10 develop cancer
BRCA2 = 4/10 develop cancer 

Overall penetrance = 50%

Question 12

What approach is used used to detect mutations in the BRCA1/2 genes?
- why is this necessary?

Answer 12

• 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

Question 13

With the large amount of information obtained from the scanning approach, how do you determine if mutations are meaningful or just typical benign polymorphisms?

Answer 13

• Pathogenic Variants have been documented

**Those not known to be benign or pathogenic are given the label of UNCERTAIN SIGNIFICANCE

Question 14

T or F: mutations to the BRCA1/2 genes often results in loss of function

Answer 14

True

Question 15

T or F: BRCA1/2 are always sequenced together

Answer 15

True

Question 16

Where are samples drawn to look for BRCA1/2 mutations?

• DNA type
• what is sequenced

Answer 16

• 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

Question 17

What are the 3 categories of pathogenicity for mutations in BRCA genes (or any other genes)?

Answer 17

• Pathogenic
• Benign
• Uncertain Significance

Question 18

What areas of the BRCA genes are targeted when sequencing data?

Answer 18

Regions:

• Promoter
• Coding
• All areas needed for accurate splicing

**Introns are rarely used in analysis

Question 19

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

Answer 19

True, ~15% of all mutations are mutations that span several exons

Question 20

What is unique about founder populations with regard to:

• Allele Frequency
• Allelic Heterogeneity

Answer 20

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

Question 21

Compare the frequency of BRCA genes in the general population to the Ashkenazi Jew population.

• Prevalence
• Mutation location

Answer 21

General Population:

• Prevalence = 1/500
• Mutations Found in many different spots across different people

Ashkenazi Jews:

• Prevalence = 1/40
• Several common founder mutations

Question 22

How would your approach to testing an individual in the Ashkenazi Jew population differ from testing the general population?

Answer 22

General Population:
- Scanning Approach due to high amount of Allelic Heterogeneity

Ashkenazi Jew:
- Targeted approach can be used because of Reduced Allelic Heterogeneity

Question 23

T or F: 90% of mutations occur at one of 3 points on the BRCA1 and BRCA2 genes in the general population

Answer 23

False, this is ONLY true for the Ashkenazi Jew population that has reduced allelic heterogeneity

Question 24

If a targeted test (for an Ashkenazi Jew) for a mutation in the BRCA gene comes back negative, what is the next step?

Answer 24

• Use a scanning approach

Question 25

What are 2 strengths of the scanning approach to Genetic Testing for BRCA1/2?

Answer 25

1. Its Comprehensive and Powerful method for detecting mutations (in BRCA1/2) 2. Gene Panels Provide Options for Expanded Genetic Testing (outside of BRCA1/2)

Question 26

What are 3 limitations to the scanning approach to Genetic Testing for BRCA1/2?

Answer 26

1. Not all mutations will be found 2. Some variants are difficult to interpret 3. More genes sequenced the greater the possibility of encountering VUS (variants of uncertain significance)

Question 27

Does having a negative test for a BRCA1/2 test rule out hereditary risk of getting breast cancer?

Answer 27

NO, there are other heritable mutations that are not included in this test

Question 28

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?

Answer 28

- 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

Question 29

How does finding a variant of unspecified significance (VUS) affect your care plan for the patient?

Answer 29

It does NOT have any impact on the care plan, you just go back to treating how you were before the test

Question 30

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?

Answer 30

1. Test (an) AFFECTED RELATIVE(S) of the consultand | 2. Look fore same mutation in the consultand

Question 31

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?

Answer 31

The consultand is then at population risk of getting breast cancer

Question 32

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?

Answer 32

Without a sample from relative, you don't know where to look for the mutation so the result is INCONCLUSIVE

Question 33

T or F: failure to find pathogenic variants in a patient rules out the hereditary risk of breast cancer?

Answer 33

False