2, 7 or 70 Genes? What Determines the Value of Genetic Testing?

Maria is 43 and has recently been diagnosed with breast cancer. She and her treating physicians want to investigate whether she has a hereditary predisposition to the disease. Depending on the gene involved, this information could influence her treatment options and help assess cancer risk among her relatives.

Greece's National Organisation for Healthcare Services Provision (EOPYY) reimburses genetic testing for BRCA1 and BRCA2, subject to a patient co-payment. Yet commercially available tests can now analyse dozens of genes simultaneously.

After discussing the options with her clinical team, Maria chooses a broader multigene panel. No pathogenic variant is found in BRCA1 or BRCA2. Instead, testing identifies one in CHEK2, a gene associated with an increased risk of breast cancer.

Her 35-year-old sister subsequently undergoes targeted testing and learns that she carries the same variant. Until then, her family history-based risk assessment had not led to a recommendation for enhanced breast screening. Could this genetic finding change that recommendation?

The case is hypothetical, but the dilemma is familiar in clinical practice. It becomes particularly interesting when we consider that CHEK2 was excluded from a recent European expert proposal for routine first-line germline testing in breast cancer.

Why Was CHEK2 Left Out?

In 2025, an international expert group working under the auspices of the European Society for Medical Oncology (ESMO), specifically its Precision Oncology Working Group, published recommendations on which genes should be included in first-line germline testing as part of routine oncology care (1).

The group identified six genes with high or moderate expected clinical utility: BRCA1, BRCA2, PALB2, RAD51C, RAD51D and TP53, with the latter included for patients diagnosed before the age of 40. It also considered adding BRIP1, bringing the proposed panel to as many as seven genes.

The composition of this panel may seem surprising, even to professionals familiar with hereditary breast cancer. BRIP1 is not considered a major breast cancer predisposition gene. By contrast, CHEK2 and ATM, which were left out, have well-established associations with the disease.

The explanation lies in how the expert group assessed clinical utility.

Knowing that a pathogenic variant increases cancer risk is not enough. We also need to ask what can be done with that information and, crucially, how strong the evidence is that subsequent interventions actually benefit patients.

RAD51C, RAD51D and BRIP1 are associated with an increased risk of ovarian cancer. For appropriately selected carriers, risk-reducing removal of the fallopian tubes and ovaries can be an important preventive option. Evidence supporting the expected benefit comes partly from studies of BRCA1/2 carriers, for whom the effectiveness of this intervention has been investigated more extensively.

For CHEK2 and ATM, the working group concluded that the evidence was not yet sufficient to establish that routinely identifying pathogenic variants in these genes, followed by the interventions that might result, would provide an additional reduction in mortality sufficient to justify their inclusion in the standard first-line panel.

To understand this decision, we need to consider the purpose of the recommendations. The group sought to define a standard first-line panel that could be offered routinely to eligible patients with breast cancer, rather than a different panel for every family. More specialised genetic assessment would remain appropriate when additional indications arise from personal or family history.

When testing is offered on this scale, the choice of genes influences not only what we might detect, but also what happens afterwards. Identifying a pathogenic variant may lead to testing of relatives, long-term surveillance or risk-reducing interventions. These can provide substantial benefits, but may also involve potential harms, burdens and demands on healthcare resources. The ESMO working group therefore placed particular emphasis on the evidence supporting the benefits of interventions that might follow from routine testing.

Excluding CHEK2 and ATM from the proposed routine panel does not mean that testing them lacks clinical value. Rather, when a test is intended for thousands of patients, its expected benefits must be weighed against the potential consequences of acting on its results.

There is another important consideration. The strength of direct evidence is not identical for every gene included or considered for inclusion. Estimates of the benefits of preventive surgery for carriers of RAD51C, RAD51D and BRIP1 rely partly on extrapolation from other hereditary cancer predisposition groups.

This does not invalidate the recommendations. It illustrates, however, that even rigorously evidence-based guidance involves judgement: what evidence is sufficient, how much uncertainty are we prepared to accept, and which outcomes matter most?

Can Genetic Information Be Useful Before Its Full Clinical Benefit Is Established?

Consider Maria's sister again.

Carrying a pathogenic CHEK2 variant does not, by itself, establish whether she needs an intensified breast screening programme, such as annual MRI alongside mammography at the appropriate age.

Risk varies between variants within the same gene. Some, such as p.Ile157Thr, are associated with a lower risk of breast cancer and are not, on their own, sufficient to justify enhanced surveillance (2). Family history also remains important, even after a positive genetic test result.

Nevertheless, genetic information can substantially change an individual's risk assessment.

In a 2020 study, researchers estimated breast cancer risk among unaffected female relatives of CHEK2 carriers (3). Based on family history alone, approximately 15% of first-degree relatives had an estimated lifetime breast cancer risk exceeding 20%. When information about the pathogenic variant identified in the affected family member was incorporated into the model, that proportion rose to approximately 55%.

The study did not establish that all these relatives carried the variant, nor did it demonstrate that MRI screening reduced their mortality. Its finding was different: knowledge of a familial pathogenic variant can substantially alter risk estimates and, consequently, which relatives may be considered for enhanced breast screening.

But how much benefit does that additional screening offer?

A modelling study published in 2022 estimated that annual breast MRI beginning between ages 30 and 35, combined with mammography from age 40, could reduce breast cancer mortality by approximately 54–60% among carriers of pathogenic variants in ATM, CHEK2 and PALB2, compared with no screening (4).

Mammography alone was already associated with an estimated mortality reduction of 36–39%, also compared with no screening. Adding MRI therefore offered a smaller, but potentially important, additional benefit. More intensive screening, however, also resulted in more false-positive findings and biopsies that ultimately proved benign.

The crucial limitation is that these results come from mathematical models, not from directly observed reductions in mortality.

Can we act on genetic information when the benefits of subsequent interventions have not yet been demonstrated with the level of certainty we would ideally want? If so, for which patients, and under what circumstances?

This uncertainty lies at the heart of the debate over genetic testing.

What Do the Guidelines Actually Disagree About?

American guidelines approach the question from a different starting point.

In 2024, the American Society of Clinical Oncology (ASCO), together with the Society of Surgical Oncology, recommended offering BRCA1/2 testing to all patients newly diagnosed with breast cancer at age 65 or younger, as well as selected older patients (5).

A separate ASCO guideline addressing the selection of multigene testing panels recommends choosing genes according to personal and family history and their potential clinical utility (6). Testing additional genes may be justified when the anticipated benefits can be identified and the uncertainties arising from the results can be appropriately managed.

Guidelines from the National Comprehensive Cancer Network (NCCN), meanwhile, recognise that findings in CHEK2 and ATM can influence surveillance recommendations for carriers, depending on the specific variant and the individual's overall risk assessment (7).

These are not necessarily opposing scientific positions. Rather, they address different parts of the same clinical process.

The ESMO working group sought to establish which genes should be included in a standard first-line test offered routinely to large numbers of patients. ASCO's guidance addresses how to select appropriate genes for an individual patient. NCCN provides, among other recommendations, guidance on managing individuals in whom a pathogenic variant has already been identified.

Selecting the initial panel, deciding whether further investigation is warranted and determining how to use the findings are connected stages of genetic assessment. A standardised test may provide a starting point without necessarily being sufficient for every patient or family.

In Greece, the Problem Begins Earlier

Internationally, the discussion centres on which genes warrant routine testing, how strong the supporting evidence should be and how to balance potential benefits against possible consequences.

In Greece, a more immediate question arises: which tests can patients actually access without having to pay most of the cost themselves?

Routine EOPYY reimbursement for hereditary cancer predisposition testing covers BRCA1 and BRCA2, subject to eligibility criteria that include breast cancer diagnosed before age 45 (8). Patients are required to make a financial contribution, while broader multigene panels are not covered by an equivalent general reimbursement scheme.

The three numbers in the title therefore represent three different starting points.

Two largely reflects a public reimbursement decision. Seven comes from a scientific assessment of which genes should be included in a routinely offered first-line test. Seventy is a symbolic number, rather than a specific recommended panel, representing the much broader multigene tests now available commercially.

They are not three answers to the same question.

Adopting the ESMO working group's approach in Greece would not necessarily mean offering less genetic testing. On the contrary, its recommendations could provide a starting point for expanding public reimbursement beyond BRCA1/2.

Such an expansion, however, would need to be accompanied by clear criteria for first-line testing, access to reimbursed further investigation when clinically indicated, and appropriate genetic counselling. Simply reimbursing a larger panel would not, by itself, guarantee better care.

Genetic testing does not end when a laboratory issues its report. The result may prompt testing of relatives, reassessment of cancer risk or discussions about preventive interventions involving uncertainty, financial costs and significant personal consequences.

Ensuring access to this ongoing care is just as important as ensuring access to the test itself.

The Decision That Matters

Returning to Maria's 35-year-old sister, what would a positive CHEK2 result actually mean for her?

The first step would be to establish exactly which variant she carries and what is known about its association with breast cancer. We would assess her complete family history and any additional factors influencing her risk. We could then discuss whether her overall risk assessment warrants enhanced surveillance, potentially involving additional breast imaging, while explaining both the expected benefits and the limitations of the available evidence.

A pathogenic variant would not automatically lead to the same recommendation for every woman. It could, however, substantially change her estimated risk and, potentially, the decisions made about her surveillance.

There is little value in testing more genes simply because the technology allows us to. We should be able to explain why particular genes have been selected, why others have been left out, and what might change depending on the results. When the clinical evidence warrants it, there must also be a pathway for extending the investigation.

And when further genetic testing is clinically justified, access to it should not depend primarily on a patient's ability to pay.

References

1. Turnbull C, et al. Breast cancer germline multigene panel testing in mainstream oncology based on clinical–public health utility: ESMO Precision Oncology Working Group recommendations. Annals of Oncology. 2025;36(8):853–865. https://doi.org/10.1016/j.annonc.2025.04.012
2. Hanson H, et al. Management of individuals with germline pathogenic/likely pathogenic variants in CHEK2: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine. 2023;25(10):100870. https://doi.org/10.1016/j.gim.2023.100870
3. Weidner AE, et al. Breast cancer screening implications of risk modeling among female relatives of ATM and CHEK2 carriers. Cancer. 2020;126(8):1651–1655. https://doi.org/10.1002/cncr.32715
4. Lowry KP, et al. Breast Cancer Screening Strategies for Women With ATM, CHEK2, and PALB2 Pathogenic Variants: A Comparative Modeling Analysis. JAMA Oncology. 2022;8(4):587–596. https://doi.org/10.1001/jamaoncol.2021.6204
5. Bedrosian I, et al. Germline Testing in Patients With Breast Cancer: ASCO–Society of Surgical Oncology Guideline. Journal of Clinical Oncology. 2024;42(5):584–604. https://doi.org/10.1200/JCO.23.02225
6. Tung N, et al. Selection of Germline Genetic Testing Panels in Patients With Cancer: ASCO Guideline. Journal of Clinical Oncology. 2024;42(21):2599–2615. https://doi.org/10.1200/JCO.24.00662
7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. Version 1.2027, 31 August 2026. https://www.nccn.org/guidelines/category_2
8. EOPYY. Prescribing and Performing BRCA1/2 Genetic Testing. Circular DB3B/F11/oik.9744, 20 April 2026. English translation of the official Greek title. https://www.eopyy.gov.gr/media/zdkfvigd/rpe5oks7m-52g.pdf