Interpreting Moderate-Risk Genes in Breast Cancer Care

Reviewed by Ann Dietrich, MD, FAAP, FACEP

Multigene germline testing is now routine in breast cancer, and that has created a new clinical problem. The hardest results to use well are often not BRCA1 or BRCA2, but the moderate-penetrance findings that sit in the space between clearly high-risk syndromes and largely nonactionable information. Current American Society of Clinical Oncology-Society of Surgical Oncology (ASCO-SSO) guidance states that testing for moderate-penetrance breast cancer genes offers no benefit for treatment of the index breast cancer, but it may inform the risk of a second primary cancer or family risk assessment. The same guidance also states that variants of uncertain significance should not change treatment. That combination is exactly why these results are so easy to misinterpret in daily practice.

In breast cancer care, moderate-risk genes usually function as risk modifiers. They matter for surveillance of remaining breast tissue, contralateral breast cancer counseling, cascade testing, and survivorship planning, even when they do not independently dictate systemic therapy or local treatment.

What counts as a moderate-risk gene in breast cancer

The National Cancer Institute’s (NCI’s) Physician Data Query (PDQ) currently places CHEK2, BRIP1, RAD51C, RAD51D, and ATM among the moderate-penetrance genes associated with increased breast and/or gynecologic cancer risk. The same summary notes that genes such as CHEK2 and ATM are associated with a 20% or higher lifetime risk of breast cancer, while also emphasizing that the clinical actionability of many moderate-risk findings remains uncertain and is still being refined. In other words, “moderate-risk” does not mean unimportant. It means the gene usually matters most when interpreted in clinical context rather than in isolation.

In day-to-day breast cancer clinics, ATM and CHEK2 are the moderate-risk results most likely to influence counseling and follow-up. By contrast, BRIP1 is a good example of why panel literacy matters. NCI notes that BRIP1 shows odds ratios for breast cancer below 2.0 in several studies and that there is a growing consensus that BRIP1 is not a moderate- to high-risk breast cancer susceptibility gene, even though it is clearly relevant for ovarian cancer risk. A positive BRIP1 result, therefore, should not be casually folded into the same breast cancer conversation as CHEK2 or ATM.

It is also important not to blur moderate-risk genes with non-BRCA high-penetrance genes. Current ASCO-SSO guidance specifically identifies PALB2, TP53, PTEN, STK11, and CDH1 as high-penetrance genes beyond BRCA1/2 that can meaningfully affect management decisions in breast cancer. Misclassifying PALB2 as “moderate-risk” understates its importance, while treating CHEK2 or ATM as if they carry PALB2-level implications tends to drive overtreatment. Good interpretation starts with getting the penetrance category right. 

Why moderate-risk findings are harder to use than BRCA results

BRCA-associated breast cancer has a clearer clinical framework. There are established treatment implications, mature risk-management pathways, and stronger long-term data on second-primary risk. Moderate-risk genes are different. ASCO-SSO explicitly states that moderate-penetrance testing does not benefit treatment of the index breast cancer, even though it may inform future cancer risk and family counseling. That means these findings often arrive in the chart without a built-in treatment algorithm, leaving the oncology team to decide how much weight the result should carry in surgical discussions, survivorship planning, and family communication. 

The testing process itself adds complexity. ASCO’s panel-selection guideline notes that simultaneous testing of multiple genes can be more efficient when more than one syndrome is plausible, but it also emphasizes the downside of broader panels. Smaller panels avoid genes with uncertain clinical validity and limit the number of variants of uncertain significance, which may lead to misinterpretation and overtreatment. The companion ASCO Clinical Insights article makes the same point more bluntly. Very large panels can identify genes tied to other syndromes or to poorly established cancer associations, and that can create unexpected and clinically distracting findings in a patient whose immediate problem is breast cancer.

This is why counseling is not optional. NCI’s risk-assessment summary states that pretest genetic counseling helps patients understand testing options and potential outcomes, while posttest counseling helps explain the implications for both the patient and relatives. That matters even more with moderate-risk genes, because the question is rarely just “positive or negative.” It is usually “positive for what, how much risk, and what changes now?” Without that framework, a moderate-risk result can create more anxiety than usable guidance. 

Why older BRCA-only results deserve a second look

A substantial number of patients with breast cancer still carry earlier germline results that effectively only answered whether BRCA1 or BRCA2 was detected at the time. For some survivors, that test was performed before modern multigene panels were routinely used, before non-BRCA penetrance estimates were better characterized, or before there was broad awareness that moderate-risk genes could change follow-up recommendations. NCI reports that in two studies of women who had previously tested negative for BRCA1/2, reflex multigene testing identified pathogenic variants in additional genes in 8% to 11% of cases. A historical negative BRCA result should therefore not be treated as the end of hereditary assessment in every patient with breast cancer.

At the same time, retesting should still be deliberate. NCI notes that multigene testing is especially useful when there are multiple syndromes or genes on the differential diagnosis list, and ASCO’s Clinical Insights article warns that excessively broad testing without phenotype support can uncover unexpected syndromic findings and raise the probability of variant of uncertain significance (VUS) results. The best retesting strategy is not simply “larger than before.” It is “broad enough to answer the real hereditary question.”

CHEK2 is common, clinically relevant, and easy to overcall

CHEK2

CHEK2 is one of the most frequently encountered moderate-risk genes in breast cancer practice, and it is one of the most commonly mishandled. NCI’s PDQ summary describes CHEK2 as a DNA damage response gene and notes that overall studies have found an approximately 1.5-fold to 3-fold increased risk of female breast cancer. The same summary cites a combined analysis showing a significant 2.3-fold excess risk, and a meta-analysis showing an odds ratio of 2.75 for CHEK2 1100delC heterozygotes. These are not trivial numbers, but they are not BRCA-level numbers either. The result is meaningful, yet it still requires context. 

That context is often family history. NCI notes that a meta-analysis estimated breast cancer risk of 42% by age 70 years in women carrying CHEK2 1100delC who also had a family history of breast cancer, and a Polish study showed risk gradients that rose from 20% with no family history to 44% when both first- and second-degree relatives were affected. ACMG’s CHEK2 practice resource makes the same conceptual point. CHEK2 cancer risk should be viewed as a continuous variable influenced by family history and other modifiers, so early detection and prevention should be guided by personalized risk estimates rather than by the gene label alone. This is the core interpretive principle for CHEK2 in breast cancer care.

CHEK2 also has a phenotype pattern worth remembering. Large gene-association studies have shown that ATM and CHEK2 variants are more strongly associated with estrogen receptor–positive disease than with estrogen receptor–negative disease. That does not make CHEK2 an estrogen receptor (ER)-positive-only gene, but it does help explain why many CHEK2-associated breast cancers show up in clinics that would not otherwise look genetically dramatic.

ATM has real implications, but not the ones many clinicians first assume

ATM

ATM is the other moderate-risk result that commonly alters breast cancer counseling. NCI reports odds ratios around 2 for breast cancer in ATM heterozygotes, including 2.10 in one large international study and 1.82 in a large U.S. study. NCI also notes an association between ATM pathogenic variants and estrogen receptor–positive tumors, and cites modeled cumulative breast cancer risks of 6.02% by age 50 years and 32.83% by age 80 years. Those figures make ATM clinically important, but they still support individualized risk assessment rather than automatic escalation of therapy. 

ATM is frequently overinterpreted in radiation discussions because of the biology of ataxia-telangiectasia. NCI directly addresses this and states that there is insufficient evidence to recommend against radiation therapy in carriers of a single ATM pathogenic variant. That is an important distinction. The radiosensitivity seen in the recessive syndrome should not be casually transferred to every heterozygous ATM carrier with breast cancer. NCI also notes that current National Comprehensive Cancer Network-based management includes annual mammography starting at 40 years of age with consideration of breast MRI beginning at age 30 to 35 for women with an ATM pathogenic variant.

ATM also illustrates another important interpretive point: variant-specific risk is real. NCI notes that while most ATM pathogenic variants confer moderate breast cancer risk, the c.7271T>G missense variant appears to carry higher risk than many other ATM variants. That is another reason a one-line chart summary such as “ATM positive” is not enough. The gene matters, but the variant, family history, and clinical scenario matter too. 

BARD1, RAD51C, RAD51D, and BRIP1 require more context than most reports convey

The newer or less frequently encountered moderate-risk genes are where interpretation becomes even more phenotype-dependent. Large gene-association studies have shown that BARD1, RAD51C, and RAD51D are more strongly associated with estrogen receptor-negative and triple-negative breast cancer, whereas ATM and CHEK2 lean toward ER-positive disease. That does not mean every ER-negative breast cancer should trigger the same panel or the same management response, but it does mean that subtype context should influence how clinicians interpret non-BRCA findings. A BARD1 or RAD51D result does not carry the same clinical flavor as CHEK2.

Recent ACMG guidance adds another useful layer. The 2025 resource on RAD51C, RAD51D, and BRIP1 describes RAD51C and RAD51D as moderate ovarian cancer predisposition genes that are also associated with moderate risk of breast cancer, predominantly the triple-negative subtype. That framing is helpful in breast cancer clinics, because it reminds clinicians that some “breast panel” findings may be more important for ovarian-risk counseling and family cascade management than for the current breast cancer treatment plan. BRIP1 sits even more clearly in that category, given NCI’s note that it is increasingly not considered a moderate- to high-risk breast cancer gene. 

What moderate-risk genes should not change in the index breast cancer

Systemic therapy should not be extrapolated from BRCA

The current standard of care is clear on this point. ASCO-SSO states that testing for moderate-penetrance genes offers no benefit for treatment of the index breast cancer. A related hereditary breast cancer management summary also notes that there are currently no robust data to support the use of PARP inhibitors for breast cancer patients with mutations in moderate-risk genes. Clinically, that means clinicians should resist the temptation to reason from DNA-repair biology alone and assume that CHEK2 or ATM should automatically be treated like germline BRCA-associated breast cancer. Until evidence and labeling change, moderate-risk results are not routine systemic-therapy determinants. 

Local therapy should not be determined by gene status alone

The ASCO- American Society for Radiation Oncology (ASTRO)-SSO hereditary breast cancer guideline states that for women with newly diagnosed breast cancer who carry a mutation in a moderate-penetrance breast cancer susceptibility gene, mutation status alone should not determine local therapy decisions for the index tumor or contralateral risk-reducing mastectomy. That recommendation is one of the most important guardrails in the field. A positive moderate-risk result should enrich the discussion about future risk, but it should not function as a one-step instruction to convert breast-conserving options into mastectomy.

That same principle supports continued use of breast-conserving therapy when otherwise appropriate. ASTRO’s summary of the hereditary breast cancer guideline notes that patients with mutations in moderate-risk genes should be offered breast-conserving therapy as one choice after counseling, and that radiation therapy should not be withheld in ATM carriers if breast-conserving therapy is planned. In practical terms, moderate-risk status should guide nuance, not eliminate standard options. 

VUS is not a treatment result

A variant of uncertain significance is not a stealth pathogenic variant. ASCO-SSO states that VUS should not change treatment and should be followed over time for possible reclassification. NCI’s counseling summary similarly notes that VUS findings often reflect limited penetrance data, discordant phenotype, or a higher background rate of ambiguity with broader testing. A VUS should not be used as the basis for irreversible breast surgery or for rewriting an otherwise standard systemic-treatment plan.

What moderate-risk genes should change in breast cancer care

Surveillance of remaining breast tissue

Where moderate-risk genes do often matter is survivorship imaging. The ASCO-ASTRO-SSO hereditary breast cancer guideline recommends that patients with mutations in moderate-penetrance genes who do not undergo bilateral mastectomy should receive high-risk screening of the remaining breast tissue with annual mammogram and MRI. In many patients with breast cancer, the most immediate value of a moderate-risk result is in the surveillance plan that starts after local therapy is completed.

Contralateral breast cancer counseling

Gene-specific contralateral risk is another major place where these findings matter. In the prospective CARRIERS study, CHEK2 pathogenic variant carriers had a significantly increased risk of contralateral breast cancer, with a hazard ratio of 1.9 and a 10-year cumulative incidence of 7.9%. Among premenopausal CHEK2 carriers, the estimated 10-year cumulative incidence was 13%, whereas the postmenopausal estimate was 4%. ATM carriers, by contrast, did not have a significantly increased contralateral breast cancer risk, and their 10-year cumulative incidence was 4.0%, essentially similar to noncarriers in that study. That is why CHEK2 and ATM should not lead to the same contralateral surgery conversation. 

This is also where age and subtype matter. The same CARRIERS analysis showed higher contralateral risks in BRCA1/2 carriers and in PALB2 carriers with ER-negative breast cancer, underscoring that moderate-risk genes should be interpreted in a hierarchy, not as a single bucket of “positive panel” findings. For clinicians, the practical lesson is simple: contralateral risk discussions should be gene-specific, age-specific, and phenotype-specific. A moderate-risk finding should refine individualized counseling.

Family risk assessment and cascade testing

Even when a moderate-risk gene does not change the current treatment plan, it may still be highly relevant to the family. ASCO-SSO specifically notes that moderate-penetrance testing may inform family risk assessment, and NCI’s counseling summary emphasizes that posttest counseling should explain implications for relatives as well as for the patient. In breast cancer care, that means the result belongs not only in the oncology note but also in a clear plan for referral, cascade communication, and risk-based screening of relatives when appropriate. 

Family history, subtype, and models are what make moderate-risk genes clinically usable

ASCO’s panel-selection guideline emphasizes that appropriate germline testing depends on accurate family history, and that when more than one gene is relevant on the basis of personal or family history, multigene testing should be offered. The same guidance also notes that smaller panels can be preferable when the phenotype is narrower, because they reduce uncertain findings. That is especially important for moderate-risk genes. Their meaning is often inseparable from the pedigree. A CHEK2 result in a patient with multiple affected first-degree relatives is not the same as the same gene in a patient with an otherwise unremarkable family structure. 

Risk models can help translate that principle into care. NCI notes that BOADICEA/CanRisk incorporates both BRCA and non-BRCA genes, including CHEK2, ATM, and PALB2, and that the IBIS/Tyrer-Cuzick model includes both genetic and nongenetic factors. For moderate-risk genes, these models are often more useful than simple penetrance labels because they turn a gene result plus family history plus clinical covariates into an absolute risk estimate that can actually guide MRI recommendations, survivorship imaging intensity, and discussions about risk-reducing surgery. 

NCI also highlights how strongly additional modifiers can shift interpretation. After incorporation of a polygenic risk score, 30% of individuals with a CHEK2 pathogenic variant and nearly half of those with an ATM pathogenic variant fell below a 20% lifetime breast cancer risk estimate. In the same summary, 52.5% of ATM carriers and 69.7% of CHEK2 carriers without a first-degree relative with breast cancer had an estimated less than 20% lifetime risk of breast cancer. A separate comprehensive risk assessment study likewise found that breast cancer risks for CHEK2 and ATM carriers are modified by polygenic risk score and individual clinical factors. The clinical takeaway is that gene-only interpretation will often overestimate risk for some carriers and underestimate it for others. 

Pretest and posttest counseling matter more as panels get broader

NCI’s risk-assessment summary emphasizes the reason counseling is so important in multigene testing. Pretest informed consent should cover the genes being tested, possible outcomes, the likelihood of uninformative results, and the possibility of identifying variants of uncertain significance. NCI also notes that multigene testing can be especially useful when more than one syndrome is on the differential diagnosis list or when family history does not fit a single classical syndrome. That is exactly the environment in which moderate-risk genes are usually found.

The same broader testing strategy can create unintended consequences if it is not matched to the phenotype. ASCO’s Clinical Insights article notes that very large panels may include genes associated with other hereditary syndromes, such as Lynch syndrome or CDH1-associated hereditary diffuse gastric cancer, and that testing such genes in a patient with breast cancer but no suggestive personal or family history is effectively population screening. It also notes that including genes with less well-established associations increases the probability of a VUS result.

A practical framework for interpreting moderate-risk genes in clinic

The first step is to verify what the report actually says. Pathogenic and likely pathogenic variants belong in management discussions. VUS does not. The second step is to place the gene in the right penetrance category. PALB2 is not CHEK2, and CHEK2 is not ATM in every setting. The third step is to ask the most important question in breast cancer care: does this result change current treatment, future surveillance, or family management? For most moderate-risk genes, the answer is rarely “current systemic therapy,” often “future surveillance,” and frequently “family counseling.” 

The fourth step is to estimate absolute risk instead of reacting to the gene name. Use age, menopausal status, tumor subtype, variant type when known to matter, and family history. For CHEK2, contralateral risk is real and may be clinically meaningful, especially in younger patients. For ATM, routine avoidance of radiation is not supported, and contralateral risk appears much closer to baseline. Models such as BOADICEA/CanRisk or IBIS/Tyrer-Cuzick can help transform a moderate-risk result from a vague concern into an actionable surveillance plan. 

The final step is to remember that interpretation does not end with the oncology visit. NCI emphasizes the role of posttest counseling, and ASCO-SSO recommends individualized posttest counseling for pathogenic findings. In practice, that means documenting what the gene does and does not imply, clarifying whether MRI or intensified imaging is indicated, advising whether contralateral surgery discussion is warranted, and making sure relatives know that a moderate-risk gene is still a meaningful hereditary finding.