Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2

Critical Review Questions



Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2,

then coordinate with your partner to meet and complete the following questions:

1.   What problem does the first paragraph suggest that population-based genetic screening

could solve relative to family history- or personal history-based genetic testing?

2.   What is the proper, modern nomenclature for the three Ashkenazi Jewish BRCA1/2

mutations? To find this information, go to the ClinVar Database and search for the

mutation as listed in the paper. The correct mutation will be among the search results.

You can confirm that it’s the right one by clicking on the entry and looking at what is

listed under “Other Names.” To get you started, search ‘BRCA1 185delAG’– the correct

mutation is the third one listed. Write out the full genetic nomenclature for each

mutation, as listed at the top of the ClinVar entry (such as NM_XXXX(GENE):cDNA


3.   What is the frequency of each of these mutations in gnomAD overall? Among Ashkenazi

Jewish individuals only? Are there any homozygote carriers? Why or why not? For

simplicity, links to the gnomAD entries for each variant are provided for you:

a.BRCA1 185delAG

b.BRCA1 5382insC

c.BRCA2 6174delT

4.   The authors state that three main criteria for population screening are met by BRCA1/2-

related Hereditary Breast and Ovarian Cancer in the Ashkenazi Jewish population.

Please list these and comment on how they are met.

5.   How would your answers to question 4 differ if you were asked about these criteria in

the general (non-Ashkenazi Jewish) population?

6.   The authors note that disease risk to mutation carriers ascertained from the general

population is unknown. (Note that some studies have addressed this since the paper

was written in 2014, but we still don’t have great estimates.) Why are penetrance

estimates from high-risk families not appropriate?

7.   Why is the Ashkenazi Jewish population an easier target for population-based BRCA1/2

mutation screening than the general population?

8.   For the following questions, please skip down to page 14209, where the Methods

section can be found. What were the inclusion criteria for index subjects in this study?

9.   Family history of cancer was not an inclusion/exclusion criteria for the study. Why not?

10. Why did the study team invite a small number of non-carrier men for genetic counseling

and testing after initial testing for the 3 Ashkenazi Jewish mutations was complete?

11. Positive male carriers were provided with their results and then asked to do what? What

were the subset of negative male carriers who had confirmatory testing asked to do?

12. Please read the remainder of the methods, but you can go back to the Results section

on 14206 for the following questions. Why were the authors concerned that the men in

their study might not be representative of Israeli Ashkenazi Jewish men generally? What

did they do to evaluate this (three things)? What did they find? What did they conclude


13. Figure 1 provides an overview of study recruitment, enrollment, measurements taken,

and loss-to-follow-up. Some additional details are available in the Methods section.

Please state or calculate the following numbers. If not reported, state that.

a.Number of males contacted and offered participation in the study

b.Number of males who consented to the study

c. Proportion of carriers who were offered genetic counseling that had

confirmatory genetic testing

d.Proportion of non-carriers who were offered and accepted genetic counseling

that had confirmatory genetic testing

e.Carrier frequency among genotyped males, all 3 mutations combined

f.Total number of unique families among carrier males

14. The authors state that from the total number of unique families identified, 629

informative relatives (431 women and 198 men) were enrolled. Did all unique families

provide informative relatives to the study?

15. How should you interpret the following numbers in Table 1? Please be as detailed as

possible, and remember the essential components of reporting estimates in


a.Column 3, Row 10 (0):

b.Column 4, Row 8 (0.40):

16. What do the authors mean by “fully genotyped sibships” and “incompletely genotyped

sibships”? Why might excluding incompletely genotyped sibships introduce bias into the

estimates of cumulative incidence of breast and ovarian cancer?

17. What do the authors highlight as a notable difference between their results and those of

prior studies with respect to cancer risk among BRCA1 carriers vs BRCA1/2 carriers?

What two potential explanations do they suggest?

18. What evidence does this paper provide in favor of implementing population-based

screening for the three Ashkenazi Jewish BRCA1/2 mutations within an Israeli Ashkenazi

Jewish population? What information is missing or what else would you like to know?

19. In your opinion, is there sufficient evidence that a similar screening program should be

implemented for Ashkenazi Jewish individuals in the United States?

20. In your opinion, is there sufficient evidence that similar screening program should be

implemented for the general population in the United States (focusing on known, clearly

damaging mutations)?

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