Large-Scale Population Screening for BRCA1 and BRCA2 Ashkenazi Founder Mutations: Perspectives of Professionals Providing Oncogenetic Consultations

Abstract

Introduction

In March 2020, a nationwide population carrier screening for BRCA1/2 pathogenic variants among Ashkenazi Jewish women was initiated in Israel. We aimed to assess views regarding the program among professionals who provide oncogenetic counseling for detected carriers.

Methods

An online survey was distributed to clinical geneticists and genetic counselors.

Results

The participants’ impression was that most carriers did not comprehend the implications of a positive result when deciding to take the test. Some carriers, in retrospect, regretted taking it. Some had a known mutation carrier in the family, and some had a family history that justified a broader test (and so should not have been tested through the screening program). Eight survey participants (29%) reported they were initially against the screening program, but half of them are currently in favor of it. Most participants are unsatisfied with the way the screening is conducted and suggested various improvements. Emotional distress of carriers, as assessed by participants, was higher for those detected by the screening program, compared to those tested after oncogenetic counseling. No association was found between the age, profession, and prior experience of participants and their responses.

Conclusions

While the general attitude toward the screening program is positive, most professionals feel the need to improve the current screening program by defining exclusion criteria, providing comprehensive pretest information and adding other BRCA1/2 founder mutations, as well as expanding the screening to include ethnicities other than Ashkenazi Jews.

Introduction

BRCA1 and BRCA2 are tumor suppressor genes that function in DNA double-strand break repair in the homologous recombination pathway. These are the most common genes implicated in hereditary breast and ovarian cancers [1–3].

Pathogenic variants in the BRCA1 and BRCA2 genes increase the risk for breast and ovarian cancers as well as other malignancies including male breast cancer, prostate cancer, pancreatic, and gastric cancers. Identification of mutation carriers enables tailored recommendations for surveillance for early detection of cancer and risk reduction measures such as clinical breast examination, breast imaging, and salpingo-oophorectomy [4].

The prevalence of BRCA1/2 pathogenic variants in specific populations, such as individuals of Ashkenazi Jewish (AJ) descent, is increased due to a founder effect. The reported prevalence of carriers among these individuals is 1:40 [5–8].

Among Ashkenazi Jews, 11% of female breast cancer cases and 40% of ovarian cancer cases are found to be carriers of one of three founder pathogenic variants in BRCA1/2: BRCA1 c.68_69delAG (NM_007294.4) (BIC: 185delAG); BRCA1 c.5266dupC (NM_007294.4) (BIC: 5382insC), and BRCA2 c.5946delT (NM_000059.4) (BIC: 6174delT). These three mutations account for up to 95% of pathogenic variants identified in AJ in these genes [9]. As previously reported, the frequency of these three variants among AJ range from 0.96% to 1.14% for BRCA1 c.68_69del, 0.13% to 0.28% for BRCA1 c.5266dup, and 1.52% for BRCA2 c.5946del [5–7, 10].

Due to the high prevalence of BRCA1/2 carriers among AJ, population carrier screening has been suggested. A study by Gabai-Kapara et al. [6] assessed the benefit of screening among males without a personal or family history of cancer. The cumulative risk for developing breast or ovarian cancer among carrier female relatives of carrier males with BRCA1 or BRCA2 pathogenic variants by ages 60 and 80 was 0.60 ± 0.07 and 0.83 ± 0.07, respectively, for BRCA1 carriers and 0.33 ± 0.09 and 0.76 ± 0.13, respectively, for BRCA2 carriers. A study that assessed population screening among 2,167 AJ in Australia found that only 2 of the 28 women who were found to be carriers by the screening program had a significant family history of cancer [11].

In 2020, a nationwide population carrier screening program for BRCA1/2 mutations among AJ women was initiated in Israel. The screening model is based on the self-reported ethnicity of women regarding their AJ origin, the lack of personal history of breast, ovarian, or pancreatic cancer and having no known BRCA1/2 carriers in the family. Women who meet these criteria are offered screening by a primary healthcare provider and are tested in their health maintenance organization outpatient clinic. Pretest genetic counseling is not required. A short explanation is provided by a nurse with specific training and printed and online information is provided to participants at the time of the test. Since different kits are used by different laboratories, testing includes either 3, 13, or 14 BRCA1/2 pathogenic variants, all including the 3 common AJ founder mutations. A list of the 14 pathogenic variants included in these kits can be found in the supplementary data (online suppl. Table S1; for all online suppl. material, see https://doi.org/10.1159/000543678). Genetic counseling is given to all carries detected by the screening program.

To the best of our knowledge, this is the first state-funded carrier screening initiative for elevated cancer risk in unaffected individuals. Several studies regarding the views of carriers detected through BRCA1/2 screening programs were conducted in the past [11–13]. Studies like these offer valuable insights into the experiences of carriers identified through screening programs. However, it is also important to assess the perspectives of professionals with expertise oncogenetic counseling. Their input can highlight specific challenges related to providing genetic consultations for carriers identified through population screening who have not received prior genetic counseling. Furthermore, these professionals possess the expertise to understand and address issues related to the significance of test results in the context of the carrier’s family history.

The Israeli program is the first population carrier screening program for the AJ population that is nationwide. In this study, we aimed to assess how this program is perceived among professionals providing genetic counseling to female carriers.

Methods

An anonymous online survey was distributed to clinical geneticists and genetic counselors in all genetic institutes and health maintenance organizations in Israel, which include all health providers who give counseling to BRCA1/2 carriers detected by the screening program. The link was sent via email and text messages.

This study was conducted 3 years after the initiation of the screening program. The survey was created to evaluate the perspectives, experiences, and recommendations of clinical geneticists and genetic counselors concerning the screening program. It was shaped by the authors’ knowledge and understanding of the principles underlying the design of the screening program, with the aim of addressing key issues that needed attention. It consisted of 28 multiple choice questions, including basic participant information as well as questions designed to assess the respondents’ perspectives and experience with counseling patients. Additional questions aimed to explore their views on various aspects of the screening program such as its effectiveness, accessibility, and challenges. Some questions focused on personal impressions and feelings while providing counseling to carriers identified through the screening program. In addition, participants were offered to leave free-text comments (online suppl. material). Narrative comments were categorized by topics that highlighted common themes, along with shared suggestions and concerns.

Statistical Analysis

Fisher’s exact test was used to analyze the responses to specific questions among subgroups of the study cohort. p < 0.05 was considered statistically significant. Python statistics library version 3.5.1 (scipy.stats) was used for statistical analysis.

Results

The study cohort included 10 clinical geneticists (physicians) and 18 genetic counselors. Three additional participants did not complete the questionnaire and were therefore not included in the study. Study cohort characteristics are presented in Table 1.

Table 1.

Characteristics of the study cohort

Characteristic	Number, n = 28	Percentage
Profession
Genetic counselor	18	64
Physician	10	36
Sex
Female	25	64
Male	3	36
Age
<30 years	1	4
30–45 years	18	64
>45 years	9	32
Professional experience
0–5 years	10	36
5–10 years	8	28
>10 years	10	36
Number of consultations with carriers
≤10	16	57
11–20	7	25
>20	5	18

Participants’ Experience with the Screening Program

Participants reported counseling carriers that were younger than 25 years old or older than 75 years old (Table 2). Many had the impression that most carriers did not understand the significance of the genetic testing performed prior to being tested, only three (∼10%) replied that all women they counseled understood the significance. Many counselors’ impression was that some of the carriers would have avoided or postponed testing if they had prior knowledge of the implications of a positive result (no specific age tendency was noted in this group). Most professionals encountered carriers who already knew a family member who is a BRCA1/2 carrier. Some of the carriers detected through the screening program were found to carry a mutation other than the three AJ founder mutations. More than half of the participants replied that in some cases they recommended additional genetic testing (for pathogenic variants in other genes), based on suggestive family history. With regard to carriers’ responses, some expressed disbelief regarding the positive test result.

Table 2.

Experience of professionals who provided genetic counseling to carriers detected through the screening program

	Number	Percentage
Consulted carriers younger than 25 years of age	12	43
Consulted carriers older than 75 years of age	3	11
Consulted carriers with a known family mutation	23	82
Consulted carriers of a mutation other than the 3 founder Ashkenazi Jewish mutations	9	32
Professional’s assessment of the proportion of carriers with pretest lack of comprehension of the test significance
Most carriers	16	57
Minority of carriers	9	32
Consulted carriers who regretted taking the test	19	68
Ages of women who regretted taking the test (16 of 19 participants answered this question)
Under 25 years	3/16	19
Over 45 years	2/16	12
Variable ages	11/16	69
Consulted carriers who would have postponed testing if comprehensive pretest counseling would have been provided (according to the assessment of the counselor)	16	57
Consulted carriers who questioned test results validity	13	46
Consulted carriers who required additional testing according to a specific family history	15	53
Total cohort	28	100

Participants’ Views regarding the Screening Program

Among the study cohort, 20 were initially in favor of the screening program, while 8 answered that they were initially against it, half of which changed their views and are now in favor of it (Table 3). The majority of the participants (96.5%) were dissatisfied with the current screening method. Three (11%) stated that in their opinion the screening program should be cancelled, and twenty (71%) answered they would change the existing protocol. Participants offered several suggestions for changes needed in the program:

• (1)Limit the referral age to 25–75 years.
• (2)Improve pretest information delivery in various ways, including prior consultation with the primary physician, pretest group session, use of media aids such as online pamphlets, short movies, etc.
• (3)Develop a system to detect cases that would require pretest genetic counseling (such as family members of known carriers or family history requiring expanded testing).
• (4)Expand the program to other ethnicities and other pathogenic variants; some suggested doing so after additional research.

Table 3.

Participants views toward the screening program

	Number	Percentage
Initial attitude prior to screening initiation
In favor	20	71
Against	8	29
Change in view toward the program (at 3 years after initiation)
Initially in favor – no change	20	71
Initially against – currently in favor	4	14
Initially against – no change	3	11
Satisfied regarding the current method of screening
Yes	1	4
No	4	14
Partially	23	82
Opinion regarding the current screening protocol
In favor	6	21
Should be changed	20	71
Should the screening program be cancelled?
No	21	75
Yes	3	11
No opinion	4	14
Views regarding adjustments in the screening program
Changing the age of individuals referred for screening
Above 25	18	64
Below 75	2	7
No need to change	7	25
Prevent women with significant family history from participating in the screening and refer them to genetic consultation prior to testing
Yes	8	29
No	18	64
In favor of expanding the screening to additional ethnicities	21	75
In favor of expanding the screening to additional mutations	18	64
Total cohort	28	100

Emotional Aspects

Seventeen participants felt that the emotional distress of carriers detected through the screening program was higher compared to carriers detected after pretest oncogenetic counseling. According to the participating professionals, the most common reported reactions expressed by carriers were concern regarding the significance to family members, shock and difficulty to accept the results, distress, and grief. Many carriers were interested in receiving appropriate follow-up recommendations. Most participants felt that some of the carriers would have avoided or postponed testing if they had prior knowledge of its implications. Nearly 70% of survey participants stated that they experienced greater difficulty in counseling a carrier from the screening program compared to a carrier who received pretest genetic counseling, while 25% stated that they did not find a difference in counseling these two groups.

Participants’ Knowledge

Survey participants were asked what were the criteria for including the three AJ mutations in the program. One-third of those who answered this question marked all the criteria correctly. The other two-thirds missed one or two of the four criteria: high incidence, high penetrance in the absence of a family history, high detection rate in the AJ population, and low-cost, and availability of the test.

Participants’ Narrative Comments and Concerns

The narrative comments of the participants mainly focused on the carriers’ limited understanding of the test’s implications prior to being tested. They highlighted the inadequate explanations provided to participants, which can lead to women undergoing testing without much consideration. In addition, the lack of sufficient designated BRCA1/2 carrier follow-up clinics was noted.

Concerns were also raised regarding false reassurance of negative screening results. Specifically, participants commented on the necessity to prioritize cases requiring further testing due to a strong family history. They also suggested including an appropriate disclaimer with test results to emphasize the need for additional counseling in cases of a positive family history. Additionally, there was concern about the over-referral of cases with non-suggestive family histories, which could lead to an overload of referrals to genetics institutes.

Factors Associated with Participants’ Responses

We did not find any significant association between participants’ characteristics (including years of experience, number of consultations given to BRCA1/2 carries found in the screening program, age or profession) and their views regarding the screening program before it started, the option of cancelling the program, preventing women with a significant family history in a first-degree relative from taking the test and the option to expand the program to additional ethnicities and additional pathogenic variants. The statistical analysis is presented in online supplementary Table S2a/b.

Discussion

This study includes reported experience, views and suggestions of 10 physicians and 18 genetic counselors who comprise the vast majority of those who provide genetic counseling to carrier females detected by the BRCA1/2 screening program that was initiated in Israel in 2020 among AJ women. We estimate that these 28 individuals sufficiently represent the professional cohort providing oncogenetic consultations in Israel. Most participating professionals were generally in favor of the program. However, all had various suggestions for protocol modifications, mainly regarding the need to provide better pretest information and to restrict testing to women aged 25–75 and to those with no known carrier in the family. One specifically concerning issue is that most participants felt that some of the carriers detected by the screening program would have avoided or postponed testing if they had prior knowledge regarding implications of a positive result. In addition, concerns regarding false reassurance of negative screening results were raised. More than half of the participants recommended additional genetic testing to carriers based on a suggestive family history, at least once. This implies that women with negative screening results and a significant family history may be candidates for additional testing and may be falsely reassured by the screening test result. Although women reporting specific malignancies in first-degree relatives are referred to genetic counseling in addition to the screening test, those who receive negative screening results may not proceed with such counseling.

Population screening for BRCA1/2 pathogenic variants among unselected Ashkenazi Jews is not standard practice worldwide. However, this concept has been addressed in several studies [9, 11–14]. Weisman et al. [13] described the BRCA Community Initiative project, where AJ individuals were offered BRCA1/2 screening. The study groups were categorized as high-risk (101 individuals) or low-risk (LR) (88 individuals) based on cancer histories. The high-risk group received traditional genetic counseling/testing; the LR group was offered group genetic counseling and AJ BRCA1/2 founder mutation testing. The carrier rates were 7.9% and 2.27%, respectively. Hence, the yield for LR AJ individuals was significant. The two individuals from the LR group who were found to be carriers expressed disbelief of the positive result and asked to be retested in a different laboratory. In our study, almost half of the counselors reported this response from some of the carriers. This emphasizes the importance of a thorough and detailed explanation regarding the screening test prior to taking it.

Tiller et al. [11] reported the screening results of 2,167 AJ individuals from Australia. Of 28 (1.3%) females who were found to be carriers of an AJ founder mutation, only 2 had significant family history of cancer. Bernstein-Molho et al. [14] assessed the yield of screening for known variants in the BRCA1/2 genes and additional cancer-related genes among 1,764 individuals of multiethnic background. The BRCA1/2 pathogenic variants carrier rate was 1.8% in AJ and mixed AJ/non-AJ participants. Interestingly, this study found that a family history of cancer was not associated with a higher rate of pathogenic variants.

The first report of the Israeli national BRCA1/2 screening program was published in 2023 by Greenberg et al. [9]. The carrier rate among 13,502 women was 0.95%. Of note, only 33% of the tested women were 100% AJ by report, while the rest were part Ashkenazi.

The main concern in the current screening protocol revealed by our study is the lack of adequate information provided pretesting regarding the implications of a positive result and therefore the lack of a thorough discussion and thought process occurring during pretest genetic counseling sessions. As a result, the patients do not fully comprehend the possible outcomes of the screening test. We believe this is the leading cause of the significant emotional distress and regret of some of the carriers detected by the program. Improving the information provided to women before taking the test and ensuring their understanding should be a significant factor in alleviating possible stress and shock. In addition, additional measures should be considered such as securing the availability of mental healthcare providers as well as other professionals including obstetrician-gynecologists and breast surgeons. We believe this aspect is not limited to the Israeli BRCA1/2 screening program and should be considered in any scenario of a population carrier screening program that infers an increased risk for illness to the screened individual (as opposed to, for example, carrier screening for autosomal recessive syndromes).

Tiller et al. assessed two protocols for delivering information to women participating in AJ BRCA1/2 founder mutations screening program. One group received information via an interactive online tool and the second group attended in-person group sessions. Pretest and posttest anxiety scores were normal. Decisional regret and test-related distress were low, with no differences between protocols. Post-education knowledge was good overall; however, it was significantly higher among those who participated in the in-person sessions. This suggests that if we aim to improve pretest comprehension, we may need to focus on in-person information delivery. The effectiveness of different genetic counseling information delivery methods has been the subject of several studies. A recently published review examined interventions supporting BRCA1/2 germline genetic testing decisions [15]. The authors concluded that various modalities for delivering genetic counseling, including technology-based, written, and in-person interventions, can be as effective as traditional face-to-face counseling in improving knowledge and decreasing decisional conflict. However, the effectiveness of these different modalities on actual genetic testing uptake varied. When comparing the efficacy of different modalities for information delivery it is crucial to differentiate between information delivered by a clinician in person or via telemedicine and modes of delivery that are without a clinician’s involvement, such as bot, artificial intelligence, written material, videos, etc. Research on telemedicine (in genetic counseling) generally shows comparable effectiveness to in-person sessions with few disadvantages [16–18]. Similarly, studies on chatbot-based pretest suggest its viability and potential to expand access to care. However, further research is needed to determine optimal delivery methods [19–21]. Given the current national BRCA screening program’s reliance on nurse briefings and written materials, evaluating patient satisfaction and comprehension using diverse delivery methods, and measuring direct patient outcomes, is crucial for optimizing the program’s effectiveness.

One issue addressed in our questionnaire was participants’ views regarding expanding screening to additional ethnicities and additional pathogenic variants. About half of the participants were in favor of these suggestions. The notion of testing additional ethnicities is supported by the study of Bernstein-Molho et al. [14] that reported that although the yield of the BRCA1/2 pathogenic variants testing was higher in AJ and mixed AJ/non-AJ participants, the yield in non-AJ patients was also significant (1%).

Another concern raised by the study participants was the challenges they face when counseling carriers detected by the screening program. The emotional distress of carriers identified by the screening program is a key factor contributing to these challenges. Also, since there is no pretest counseling session, the counselor has no prior knowledge regarding personal/family history that may be crucial for personalized recommendations. As a result, the counseling session usually begins with taking the personal and family history, while carriers are anxious to receive information regarding the test result and its implications regarding themselves and their families. Pretest counseling sessions are also important for establishing personal counselor-counselee relationship and trust. Omitting this step enhances both the carriers and the counselors’ emotional difficulties. The wellbeing of counselors should also be addressed, and professional support options should be made available for them as well.

The limitations of our study include a limited cohort size (restricted by the number of professionals who practice onco-genetics in Israel) as well as a potential response bias. However, participation in the study was voluntary, confidential and the cohort included both genetic counselors and clinical geneticists who were all experienced in providing consultations to carriers detected by the national screening program.

The professional perspective alone is insufficient. Further research into the experiences of individuals undergoing BRCA screening, particularly those identified as carriers, is crucial. This would provide valuable insights into the program’s strengths and weaknesses, informing necessary modifications to the screening protocol.

Conclusion

This study provides insights into the evolving perspectives of professionals who counsel carrier females detected by the national screening program for BRCA1/2 AJ founder mutations. While attitudes have shifted in favor of the screening program, most professionals highlight the need to improve information given before testing, to provide adequate support to BRCA1/2 carriers detected through the screening program and to ensure availability of follow-up clinics. We believe that this study’s findings can facilitate revisions to the BRCA1/2 coscreening protocol to enhance effectiveness, improve professional acceptance, and support future expansion to include additional ethnicities and variants.

Acknowledgments

The authors thank Faye Schreiber for editing the manuscript. She is employed by Meir Medical Center as a scientific editor.

Statement of Ethics

The Meir Medical Center Institutional Review Board granted an exemption for the review of this study on February 14th, 2023. Hence, no reference number was received. No consent form was requested by the board. Consent was inferred by the voluntary participants in the survey.

Conflict of Interest Statement

The authors have no relevant financial or nonfinancial interests to disclose.

Funding Sources

No funding was received for conducting this study.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Yael Furman and Rivka Sukenik-Halevy. The first draft of the manuscript was written by Yael Furman and Rivka Sukenik-Halevy and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding Statement

No funding was received for conducting this study.

Data Availability Statement

The data underlying this article will be shared on reasonable request to the corresponding author.