BRCA I and II

Question 1

Are most cases of breast cancer linked hereditary mutation?

Answer 1

No, the vast majority (~90%) arise sporadically while only 5-10% are the result of mutation of genes

Question 2

What are the most common gene mutations that cause breast cancer?

Answer 2

BRCA I (70%) and BRCA II (20%). These represent the majority of hereditary cases of breast cancer (although recall that 90% of breast cancer cases arise from sporadic mutation and is not gene related)

Question 3

What do the BRCA I and II genes code for?

Answer 3

BRCA1 and BRCA2 code for nuclear proteins that play a role in responding to DNA damage and maintaining genomic integrity. Both are members of a class of genes called tumor suppressor genes

Question 4

T or F. Patients with HBOC are heterozygous for a mutation either in BRCA1 or in BRCA2 (not both!) in every cell of their body.


Answer 4

T

Question 5

Women who are heterozygous for the mutated BRCA I gene have what chance of getting breast cancer over the course of their life?

Answer 5

60%

Question 6

Women who are heterozygous for the mutated BRCA II gene have what chance of getting breast cancer over the course of their life?

Answer 6

40%

Question 7

Woman with normal BRCA genes have what chance of getting breast cancer in their life?

Answer 7

10%

Question 8

What is the inheritance mode of HBOC?

Answer 8

autosomal dominant with reduced penetrance. As with all AD disorders, an affected individual will pass the mutation to half of his/her offspring

Question 9

What is the typically penetrance of people with a BRCA I or II mutation?

Answer 9

50%

Question 10

The BRCA I gene is on what chromosome?

Answer 10

17

Question 11

The BRCA II gene is on what chromosome?

Answer 11

13

Question 12

What is the most common cause of mutation in a BRCA gene?

Answer 12

point mutation (usually truncating)

Question 13

Since most mutations of the BRCA gene are truncating, what are they considered in terms of protein function?

Answer 13

loss of function

Question 14

is a screening or targeted testing approach better for BRCA gene mutations? Why?

Answer 14

Screening because there are no predominant mutations in the general population. (i.e. there is a lot of allelic heterogeneity

Although there are some distinctions between BRCA1 and BRCA2 phenotypes, there is a lot of overlap, and the distinctions won’t be apparent in many families. For this reason, genetic testing always includes both genes. 


Question 15

What gene segments are included in the scanning approach with BRCA I and II?

Answer 15

promoter, all the coding sequences, and the regions required for accurate splicing. introns are omitted except for any specific regions where pathogenic variants have been previously documented

NOTE: as sequencing technologies continue to advance at a rapid pace, the capacity to include noncoding sequences in analysis will increase.


Question 16

Are the majority of BRCA mutations point mutations or large deletions/duplications?

Answer 16

point mutations (85%) Thus, the goal of sequencing is to identify point mutations – single base substitutions and small insertions and deletions.


Separate analyses are done to look for large deletions and similar genomic rearrangements that account for a significant minority of causative mutations

Question 17

In the general population, what is the prevalence of mutation to BCRAI or II?

Answer 17

1 in 500

Question 18

What population is especially at risk for mutation to BRCA genes? Why?

What si the prevalence in this population?

Answer 18

People of Ashkenazi Jewish ancestry. Founder effect was discussed earlier in the semester; it occurs in relatively small and isolated populations, where one or more alleles are present at a much higher than expected frequency. A relatively closed population that historically has tended to breed within itself will have an elevated proportion of shared genes (higher than the general population, but not as high as in family members. Think of it as a very large, very extended family). Indeed, a number of genetic mutations, presumably the result of founder effects, are relatively common in Ashkenazi Jewish populations. One example that we’ve mentioned previously is Tay-Sach’s disease. BRCA1 and BRCA2 mutations also are present at high frequency in this population (~1 in 40 people have a mutation). Although I’ll restrict our discussion to the Ashkenazim, there are other populations with BRCA founder effects (e.g. BRCA2 mutation in Iceland).


Question 19

T or F. In the Ashkenazi Jewish line, allelic heterogeneity is much less pronounced in mutation of BRCA genes

Answer 19

T. Almost 90% of mutations in this population can be attributed to 1 of 3 mutations

Question 20

What are the three common mutations of the BRCA gene in the Ashkenawi Jew population?

Answer 20

1) 2 bp deletion at the 5’ end of BRCA I (185delAG)
2) 1 bp insertion at the 3’ end of BRCA I (5382insC)
3) 1 bp deletionin BRCA II (6174delT)

These are all frame-shift mutations (i.e. causes truncation of the protein and loss of function)

Question 21

What is the significance of there being much less allelic heterogeneity in the mutations of BRCA i and II in the Ashkenazi Jew population?

Answer 21

a targeted testing approach is much more effective than with the general population

Question 22

What if an Ashkenazi Jew tested is homozygous normal for those three mutations?

Answer 22

Then, it is appropriate to move on to the sequencing (scanning) test, to see if the patient falls into the other ~10% of Jewish individuals who are more similar to the general population.

Question 23

What are the strengths of HBOC gene scanning?

Answer 23

gene panels offering potential for expanding testing; comprehensive; can find mutations anywhere in the gene

Question 24

What are the limitations of HBOC gene scanning?

Answer 24

VUS; mutations in introns

Question 25

If no mutation is found in BRCA1 or BRCA2, and the family history is significant, what steps should be taken (general population)?

Answer 25

it may be indicated to expand the search to include scanning (sequencing) of other genes

Question 26

What are some common genes included in an expanded gene panel for HBOC following unsuccessful BRCA scanning?

Answer 26

CDH1, PTEN, STK11, and TP53

Question 27

What are some of the drawbacks of expanded gene panels of HBOC causes?

Answer 27

The more sequence data that are generated, the more complex the interpretation, and the greater the likelihood that one or more difficult to explain variants will be uncovered

Question 28

T or F. The more genes that are sequenced, the more likely it is to encounter a VUS.

Answer 28

T. These are the rare variants that exist somewhere in the genomes of all people. At the current time, our ability to find them has outpaced our ability to understand their significance.


Question 29

What is the testing strategy for a consultand is a healthy female who is at 50% risk to inherit an apparent cancer-causing mutation in her family?

Answer 29

In this scenario, it’s always preferable to begin testing with an affected family member. This provides an additional measure of certainty, since we can assume that whatever it is we are looking for is present in the affected family member.
This point is valid for any testing that involves “discovery”, that is any test that uses a scanning approach.

Example: If her affected aunt (or mother) undergo testing, and a pathogenic variant is found (either in BRCA or another cancer gene), then we have certainty about the cause of HBOC in the family. Subsequently, a targeted test specifically for that mutation can be used for the consultand. If she doesn’t have the mutation, then there is reasonable certainty that she has avoided the 50% risk to inherit the familial mutation. Her result is a true negative. Her risk is reduced to the population level, and she can follow routine screening procedures rather than high-risk surveillance or surgical intervention