Medical Policy

Policy Num:      11.003.027
Policy Name:     Germline Genetic Testing for Gene Variants Associated With Breast Cancer in Individuals at High Breast Cancer Risk (CHEK2, ATM, and BARD1)
Policy ID:          [11.003.027] [Ac / B / M- / P- ] [2.04.126]

Last Review:      September 12, 2024
Next Review:      September 20, 2025
 

Related Policies:

11.003.030 - Genetic Testing for BRCA1 or BRCA2 for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers
11.003.028 - Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes
11.003.022 - Genetic Testing for Li-Fraumeni Syndrome

11.003.134 - Molecular Testing for Germline Variants Associated with Ovarian Cancer (BRIP1,RAD51C, RAD51D, NBN)
11.003.016 - Genetic Testing for PTEN Hamartoma Tumor Syndrome
11.003.064- Genetic Cancer Susceptibility Panels Using Next Generation Sequencing
06.001.010- Magnetic Resonance Imaging for Detection and Diagnosis of Breast Cancer

Germline Genetic Testing for Gene Variants Associated With Breast Cancer in Individuals at High Breast Cancer Risk (CHEK2, ATM, and BARD1)

SUMMARY

Description

It is estimated that 3% to 5% of women presenting for assessment for hereditary breast/ovarian cancer risk have a variant in a gene that moderately increases the risk of cancer. CHEK2, ATM, and BARD1 variants are considered to be of moderate penetrance. Female carriers of CHEK2, ATM, and BARD1 have an approximately 2- to 4-fold increased risk of developing breast cancer compared with the general population. Risk estimates may be higher in patients with a family history of breast cancer or a family history of a specific variant.

Germline genetic testing for BRCA1, BRCA2, and PALB2 is addressed separately in evidence review 2.04.02.

Summary of Evidence

For individuals with risk of hereditary breast cancer/ovarian cancer (HBOC) who receive genetic testing for a CHEK2 variant, the evidence includes studies of variant prevalence and studies of breast cancer risk. Relevant outcomes are overall survival (OS), disease-specific survival, and test validity. The available studies on clinical validity have demonstrated that CHEK2 variants are of moderate penetrance, and confer a risk of breast cancer 2 to 4 times that of the general population. Direct evidence for the clinical utility of genetic testing for CHEK2 variants in individuals with risk of HBOC was not identified. It is unclear whether the relative risk (RR) associated with the moderate penetrance variants would increase risk enough beyond that already conferred by familial risk to change screening behavior. In contrast to high-penetrance variants, there is unlikely to be a similar benefit-to-risk calculus for risk-reducing mastectomy in women with a moderate penetrance variant such as CHEK2. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with risk of HBOC who receive genetic testing for an ATM variant, the evidence includes studies of variant prevalence and studies of breast cancer risk. Relevant outcomes are OS, disease-specific survival, and test validity. The available studies on clinical validity have demonstrated that ATM variants are of moderate penetrance; moreover, ATM variants confer a risk of breast cancer 2 to 4 times that of the general population. Direct evidence for the clinical utility of genetic testing for ATM variants in individuals with risk of HBOC was not identified. It is unclear whether the RR associated with the moderate penetrance variants would increase risk enough beyond that already conferred by familial risk to change screening behavior. In contrast to high-penetrance variants, there is unlikely to be a similar benefit-to-risk calculus for preventive interventions in women with a moderate penetrance variant such as ATM. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with risk of HBOC who receive genetic testing for a BARD1 variant, the evidence includes studies of variant prevalence and studies of breast cancer risk. Relevant outcomes are OS, disease-specific survival, and test validity. The available studies on clinical validity have demonstrated that BARD1 variants are of low to moderate penetrance; BARD1 variants confer a risk of breast cancer about 2 to 3 times that of the general population. Direct evidence for the clinical utility of genetic testing for BARD1 variants in individuals with a risk of HBOC was not identified. It is unclear whether the RR associated with the low to moderate penetrance variants would increase risk enough beyond that already conferred by familial risk to change screening behavior. In contrast to high-penetrance variants, there is unlikely to be a similar benefit-to-risk calculus for preventive interventions in women with a low to moderate penetrance variant such as BARD1. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

OBJECTIVE

The objective of this review is to determine whether testing for CHEK2, ATM and BARD1 variants in individuals with a risk of hereditary breast/ovarian cancer improves the net health outcome.

POLICY STATEMENTS

Testing for CHEK2, ATM, and BARD1 variants in the assessment of breast cancer risk is considered investigational.

POLICY GUIDELINES

Criteria for Genetic Risk Evaluation

The National Comprehensive Cancer Network (NCCN) provides criteria for genetic risk evaluation for individuals with no history of breast cancer and for those with a breast cancer. Updated versions of the criteria are available on the NCCN website.

The recommended testing strategy for BRCA1, BRCA2, and PALB2 is described in review 2.04.02 (genetic testing for hereditary breast/ovarian cancer syndrome).

Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Coding

See the Codes table for details.

BENEFIT APPLICATION

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BACKGROUND

Breast Cancer and Genetics

The National Cancer Institute estimated there would be 297,790 new cases of female breast cancer (FBC) and 2,800 cases of male breast cancer (MBC) diagnosed in 2023, with an expected 43,170 deaths due to FBC and 530 deaths due to MBC.^1, Although non-Hispanic, white women are more likely to be diagnosed with breast cancer than non-Hispanic Black, Asian/Pacific Islander, American Indian/Alaska Native and Hispanic women, non-Hispanic Black women have the highest risk of breast cancer mortality.^2, Breast cancers can be classified as sporadic, familial, or hereditary. Most breast cancers are sporadic (70% to 75%), occurring in individuals without a family history of the disease. Familial cancers (15% to 25%) aggregate within families but lack clearly discernable patterns of inheritance and are likely polygenic. Hereditary cancers have discernable inheritance patterns, often occur at younger ages, may be bilateral, and comprise between 5% and 10% of breast cancers. Most inherited autosomal dominant breast cancer can be attributed to the BRCA1 and BRCA2 variants. For women who inherit a pathogenic BRCA1 and BRCA2 variant, 45% to 72% will develop breast cancer by 70 to 80 years of age; risk in men with BRCA1 and BRCA2 variants is much lower (1% and 7%, respectively).^3, Pathogenic variants in other highly penetrant genes (eg, TP53, CDH1, PTEN, STK11) contribute to a smaller number of cancers. CHEK2 and ATM are believed to be moderately penetrant^4, and BARD1 has alternatively been described as moderate, low/moderate, and low penetrance.^5,6,7,

Testing for BRCA1, BRCA2, and PALB2 is addressed in evidence review 2.04.02.

Testing for mismatch repair genes linked to Lynch syndrome is addressed in evidence review 2.04.08.

Testing for genes linked to Cowden/PTEN Hamartoma Tumor syndrome is addressed in evidence review 2.04.88.

Testing for genes linked to Li-Fraumeni syndrome is addressed in evidence review 2.04.101.

Testing for genes linked to ovarian cancer (BRIP1, RAD51C, RAD51D, NBN) is addressed in evidence review 2.04.149.

Penetrance of Pathogenic Variants

Penetrance is the risk conferred by a pathogenic variant or the proportion of individuals with the variant expected to develop cancer. Variant penetrance is considered high, moderate, or low according to lifetime risk: high (>50%), moderate (20% to 50%), and low (<20%) (corresponding relative risks of approximately ≥5, 1.5 to 5, and <1.5).^8, Variants in only a few breast cancer-susceptibility genes (BRCA1 and BRCA2 [hereditary breast/ovarian cancer syndrome], TP53 [Li-Fraumeni syndrome], PTEN [Cowden syndrome], CDH1 [hereditary diffuse gastric cancer], andSTK11 [Peutz-Jeghers syndrome]) are considered highly penetrant. For example, a woman with a BRCA1 or BRCA2 variant has a relative risk of 11 to 12 compared with the general population.^9, Penetrance can be modified by environmental factors and by family history, which is a particularly important modifier for low and moderate penetrance genes. Moreover, specific pathogenic variants within a gene may confer somewhat different risks.

Determining Variant Pathogenicity

Determining the pathogenicity of variants in a more commonly detected cancer susceptibility gene (eg, founder sequence mutations) is generally straightforward because associations are repeatedly observed. For uncommonly identified variants, such as those found in a few individuals or families, defining pathogenicity can be more difficult. For example, predicting the pathogenicity of previously unidentified variants typically requires in silico (computational) analysis predicting protein structure/function, evolutionary conservation, and splice site prediction.^10, The approach to defining pathogenicity is clearly outlined in standards and reporting guidelines.^10, Still, distinctions between a variant of uncertain significance and a pathogenic one from different laboratories may not always be identical.^11,

Genes Associated With a Moderate Penetrance of Breast Cancer

CHEK2 Gene

The CHEK2 (checkpoint kinase 2) gene is activated in response to DNA double-strand breakage and plays a role in cell-cycle control, DNA repair, and apoptosis.

In 2002, a single recurrent truncating variant in the CHEK2 gene (c.1100delC) was first reported as a cause of breast cancer, and studies have since confirmed this. The incidence of CHEK2 variants varies widely among populations. It is most prevalent in Eastern and Northern Europe, where the population frequency of the c.1100delC allele ranges from 0.5% to 1.4%; the allele is less frequent in North America and virtually absent in Spain and India. When compared with non-Hispanic, white individuals, prevalence appears to be lower in Black (odds ratio [OR] 0.17; 95% CI, 0.07 to 0.33), Asian (OR 0.14; 95% CI, 0.04 to 0.34), and Hispanic (OR 0.36; 95% CI, 0.18 to 0.62) individuals.^12,

Although most data for truncating CHEK2 variants are limited to the c.1100delC allele, 3 other founder mutations of CHEK2 (IVS2+1G>A, del5395, I157T) have been associated with breast cancer in Eastern Europe. Both IVS2+1G>A and del5395 are protein-truncating variants, and I157T is a missense variant. The truncating variants are associated with breast cancer in the Slavic populations of Poland, Belarus, Russia, and the Czech Republic. The I157T variant has a wider geographic distribution and has been reported to be associated with breast cancer in Poland, Finland, Germany, and Belarus.^13,

ATM Gene

ATM (ataxia-telangiectasia mutated), located on chromosome 11q22.3, is associated with the autosomal recessive condition ataxia-telangiectasia syndrome. This condition is characterized by progressive cerebellar ataxia with onset between the ages of 1 and 4 years, telangiectasias of the conjunctivae, oculomotor apraxia, immune defects, and cancer predisposition. Female ATM heterozygotes carriers have a risk of breast cancer about twice as high as that of the general population; however, they do not appear to have an elevated ovarian cancer risk.

BARD1 Gene

The BARD1 (BRCA1-associated RING [Really Interesting New Gene] domain) gene is located on chromosome 2 (sequence 2q34-q35). BARD1 encodes a protein that interacts with the N-terminal region of BRCA1, and BARD1 and BRCA1 can form a heterodimer by their N-terminal RING finger domains which form a stable complex.^5,BARD1 variants have been associated with an increased risk of estrogen-receptor (ER) negative breast cancer, triple-negative breast cancer, and breast cancer at a younger age (under age 50 years) in some studies but do not appear to increase risk of ovarian cancer.^4,14,

Identifying Individuals at Risk of an Inherited Susceptibility to Breast Cancer

Breast cancer risk can be affected by genetic and nongenetic factors. The risk is increased in women experiencing an earlier age at menarche, nulliparity, late age of first pregnancy, fewer births, late menopause, proliferative breast disease, menopausal hormone therapy, alcohol, obesity, inactivity, and radiation.^15, A family history of breast cancer confers between a 2- and 4-fold increased risk varying by several factors: the number and closeness of affected relatives, age at which cancers developed, whether breast cancers were bilateral, and if other cancers occurred (eg, ovarian).^16, In men, family history is associated with an increased risk of breast cancer, along with being older than 65 years, health conditions that result in elevated estrogen levels, and lifestyle factors (eg, obesity).^17, For a woman without breast cancer, the probability of detecting a pathogenic variant can be estimated from a detailed multigenerational pedigree (eg, Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm),^18, screening tools (eg, BRCAPRO,^19, Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, Family History Screen^20,21,), or by referring to guidelines that define specific family history criteria (see Supplemental Information section on Practice Guidelines and Position Statements). For women with breast cancer, family history also affects the likelihood of carrying a pathogenic variant.^18,

Variant Interpretation

Valid variant classification is required to assess penetrance and is of particular concern for low prevalence variants. While there are guidelines for variant classification, the consistency of interpretation among laboratories is of interest. Balmaña et al (2016) examined the agreement in variant classification by different laboratories from tests for inherited cancer susceptibility from individuals undergoing panel testing.^22, The Prospective Registry of Multiplex Testing is a volunteer sample of patients invited to participate when test results were provided to patients from participating laboratories. From 518 participants, 603 variants were interpreted by multiple laboratories and/or found in ClinVar. Discrepancies were most common with CHEK2 and ATM. Given the nature of the sample, there was a significant potential for biased selection of women with either reported variants of uncertain significance or other uncertainty in interpretation. In addition, discrepancies were confined to missense variants. It is therefore difficult to draw conclusions concerning the frequency of discrepant conclusions among all tested women.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. CHEK2, ATM, and BARD1 testing are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories offering to test and voluntarily listing is available through the National Center for Biotechnology Genetic Testing Registry. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

Customized next-generation sequencing panels provide simultaneous analysis of multiple cancer predisposition genes, and typically include both moderate- and high-penetrant genes.

RATIONALE

This evidence review was created in January 2015 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through July 5, 2024.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population reference No. 1

CHEK2 and Breast Cancer Risk Assessment

Clinical Context and Test Purpose

The purpose of testing for CHEK2 variants in women at high-risk of hereditary breast cancer/ovarian cancer (HBOC) is to evaluate whether an abnormal variant is present and, if so, to determine whether the variant conveys a sufficiently high-risk such that changes in surveillance and/or treatment that are likely to decrease the risk of mortality from breast cancer are warranted.

Potential benefit derives from interventions (screening, chemoprevention, risk-reducing surgery) that can prevent first breast cancer, contralateral breast cancer, or cancer in a different organ caused by the same variant. Whether benefit outweighs harms depends on the risk of developing breast cancer (first cancer or a contralateral one) and the effectiveness and the harms of interventions.

Assessing the net health outcome requires:

• That a test accurately identifies variants and pathogenicity can be determined;

• That a variant alters (increasing or decreasing) a woman's risk of developing breast cancer (including contralateral disease in women already diagnosed) sufficient to change decision making, and of a magnitude that

• Management changes informed by testing can lead to improved health outcomes.

The following PICO was used to select literature to inform this review.

Populations

Genetic testing can be considered for women at increased risk of developing hereditary breast cancer based on their family history or in women with breast cancer whose family history or cancer characteristics (eg, triple-negative disease, young age) increase the likelihood that the breast cancer is hereditary. Testing may also be considered for women from families with known variants.

The relevant population of interest in this review is patients who are undergoing assessment for HBOC syndrome.

Interventions

The intervention of interest is CHEK2 variant testing.

Comparators

The alternative would be to manage women at high-risk of HBOC with no CHEK2 genetic testing.

Outcomes

The outcomes of interest are OS, disease-specific (breast and ovarian cancer) survival, and test validity.

Study Selection Criteria

For the evaluation of the clinical validity of the tests, studies that meet the following eligibility criteria were considered:

• Included a suitable reference standard

• Patient/sample clinical characteristics were described with women at high breast cancer risk

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Risk of Developing Breast Cancer

For genetic susceptibility to cancer, clinical validity can be established if the variants that the test is intended to identify are associated with disease risk, and if so, if these risks are well quantified. ^9,  Most studies assessing the risk of breast cancer associated with CHEK2 are population- and family-based case-control studies.

Systematic Reviews

Systematic reviews of CHEK2 and breast cancer risk have been reported. A systematic review conducted by Suszynska et al (2019) included association estimates for CHEK2 variants.^23, Characteristics are shown in Table 1, and the results are shown in Table 2. The systematic review included studies published through July 2017 reporting on genetic test results of breast and ovarian cancer patients who were referred for evaluation by a multi-gene panel. Given that the Suszynska et al (2019) report included only studies reporting on test results from a panel, it does not substantially overlap with the studies described in the following section. The studies of panel results were used to calculate mutation frequencies by the gene. As a control, population mutation frequencies were extracted from the Genome Aggregation Database. In the 43 breast cancer studies included in the review, 94,845 patients contributed to the meta-analysis of CHEK2 in breast cancer patients. The OR of breast cancer for CHEK2 variants including variants c.470T>C and c.1283C>T was OR 0.96 (95% CI, 0.90 to 1.03); after excluding variants c.470T>C and c.1283C>T, the association between the remaining CHEK2 variants and breast cancer was OR 1.73 (95% CI, 1.58 to 1.89). Given that the Suszynska et al (2019) report included only studies reporting on test results from a panel, it does not substantially overlap with the studies described in the following section including other CHEK2 association studies.

An article by Schmidt et al (2016) evaluated data on CHEK2 variant status and breast cancer risk from the BCAC.^24,25, The analysis included 44,777 breast cancer patients and 42,997 controls from 33 studies in which individuals were genotyped for CHEK2 variants. The estimated odds for invasive breast cancer in patients with and without the CHEK2 1100delC variant was 2.26 (95% CI, 1.90 to 3.10).

A meta-analysis by Yang et al (2012) examined the risk of breast cancer in whites with the CHEK2 c.1100delC variant.^24, Twenty-five case-control studies conducted in Europe and North and South America published in 16 articles were analyzed, with a total of 29,154 breast cancer cases and 37,064 controls. Of the cases, 13,875 patients had unselected breast cancer, 7945 had familial breast cancer, and 5802 had early-onset breast cancer. In total, 391 (1.3%) of the cases and 164 (0.4%) of the controls had a CHEK2 c.1100delC variant. The association between the CHEK2 c.1100delC variant and breast cancer risk was statistically significant (odds ratio [OR], 2.75; 95% CI, 2.25 to 3.36). By subgroup, odds were 2.33 (95% CI, 1.79 to 3.05) for unselected, 3.72 (95% CI, 2.61 to 5.31) for familial, and 2.78 (95% CI, 2.28 to 3.39) for early-onset breast cancer.

Weischer et al (2008) performed a meta-analysis of studies on CHEK2 c.1100delC heterozygosity and the risk of breast cancer among patients with unselected (including the general population), early-onset (<51 years of age), and familial breast cancer.^26, The analysis identified prospective cohort and case-control studies on CHEK2 c.1100delC and the risk of breast cancer published before March 2007. Inclusion criteria were women with unilateral breast cancer who did not have a known multicancer syndrome, Northern or Eastern European descent, availability for CHEK2 genotyping, BRCA1 and BRCA2 sequence variant-negative or unknown status, and breast cancer-free women as controls. The meta-analysis included 16 studies with 26,488 patient cases and 27,402 controls. Presenting both fixed and random-effect models, for CHEK2 c.1100delC heterozygotes versus noncarriers, the aggregated ORs for breast cancer were 2.7 (95% CI, 2.1 to 3.4) and 2.4 (95% CI, 1.8 to 3.2) in studies of unselected breast cancer, 2.6 (95% CI, 1.3 to 5.5) and 2.7 (95% CI, 1.3 to 5.6) in studies of early-onset breast cancer, and 4.8 (95% CI, 3.3 to 7.2) and 4.6 (95% CI, 3.1 to 6.8) in studies of familial breast cancer, respectively.

Table 1. Characteristics of Systematic Reviews of CHEK2 and Risk of Breast Cancer

NR: not reported.

Table 2. Results of Systematic Reviews of CHEK2 and Risk of Breast Cancer

CI: confidence interval; NR: not reported.aExcluding variants c.470T>C and c.1283C>T.

Individual Studies Not Included in Systematic Reviews

Individual studies not included in the previous meta-analyses have also reported on the association between breast cancer development and CHEK2 variants; they are summarized in Tables 3 and 4. The number of included patients ranged from 4000 to over 95,000. The prevalence of CHEK2 variants was approximately 2% to 3% in breast cancer patients. The OR, hazard ratio (HR), or relative risk (RR) ranged from approximately 2 to 3, although it was higher in subgroups of women with a family history of breast cancer and in biallelic carriers of CHEK2 pathogenic variants.

Table 3. Characteristics of Studies of CHEK2 and Risk of Breast Cancer

BEACCON: Hereditary BrEAst Case CONtrol study; NR: not reported.

Table 4. Results of Individuals Studies of CHEK2 and Risk of Breast Cancer

BEACCON: Hereditary BrEAst Case CONtrol study; CI: confidence interval; DCIS: ductal carcinoma in situ; NR: not reported; OR: odds ratio.

Study design and conduct limitations are shown in Tables 5 and 6. Only 1 study included population-based sampling in a prospective cohort. The remaining studies were case-control studies. Several studies did not adequately describe the selection of cases and/or controls. A complete disposition of patients or samples eligible for inclusion and those appearing in the analysis was also not provided in several studies.

Table 5. Study Relevance Limitations of Individuals Studies of CHEK2 and Risk of Breast Cancer

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.BEACCON: Hereditary BrEAst Case CONtrol study; FU: follow-up.a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined).

Table 6. Study Design and Conduct Limitations of Individuals Studies of CHEK2 and Risk of Breast Cancer

BEACCON: Hereditary BrEAst Case CONtrol study; CARRIERS: Cancer Risk Estimates Related to Susceptibility consortiumThe study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience).b Blinding key: 1. Not blinded to results of reference or other comparator tests.cTest Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described.d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data.f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison with other tests not reported.

Breast Cancer Prognosis in an Individual With a CHEK2 Sequence Variant

Studies of survival between breast cancer patients with and without CHEK2 variants have shown differing results. Breast cancer patients with CHEK2 variants may have a worse prognosis than noncarriers.

Fan et al (2018) investigated the clinical relevance of CHEK2 variants in breast cancer patients.^33, In this observational study, the genomes of 7657 Chinese BRCA1- and BRCA2-negative breast cancer patients were analyzed. Researchers reported a CHEK2 germline variant rate of 0.34%, and those with the variants were significantly more likely (p=.022) to have family histories of cancer and to develop lymph node-positive and progesterone receptor-positive cancers. Limitations include sample homogeneity and retrospective design.

A study by Huzarski et al (2014) estimated the 10-year survival rate for patients with early-onset breast cancer, with and without CHEK2 variants.^38, Patients were consecutively identified women with invasive breast cancer diagnosed at or below the age of 50, between 1996 and 2007, in 17 hospitals throughout Poland. Patients were tested for 4 founder mutations in the CHEK2 gene after diagnosis, and their medical records were used to retrieve tumor characteristics and treatments received. Dates of death were retrieved from a national registry. A total of 3592 women were eligible for the study, of whom 487 (13.6%) carried a CHEK2 variant (140 with truncating variants, 347 with missense variants). Mean follow-up was 8.9 years. Ten-year survival for CHEK2-variant carriers (78.8%; 95% CI, 74.6% to 83.2%) was similar to noncarriers (80.1%; 95% CI, 78.5% to 81.8%). After adjusting for other prognostic features, the HR comparing carriers of the missense variant with noncarriers was similar, as was the HR for carriers of a truncating variant and noncarriers.

A study by Kriege et al (2014) compared breast cancer outcomes in patients with and without CHEK2 variants.^39, Different study cohorts were combined to compare 193 carriers with 4529 noncarriers. Distant disease-free survival and breast cancer-specific survival were similar in the first 6 years after diagnosis. After 6 years, both distant disease-free survival (multivariate HR, 2.65; 95% CI 1.79 to 3.93) and breast cancer-specific survival (multivariate HR, 2.05; 95% CI, 1.41 to 2.99) were worse in CHEK2 carriers. No interaction between CHEK2 status and adjuvant chemotherapy was observed.

Weischer et al (2012) reported on breast cancer associated with early death, breast cancer-specific death, and the increased risk of a second breast cancer (defined as a contralateral tumor) in CHEK2-variant carriers and noncarriers in 25,571 white women of Northern and Eastern European descent who had invasive breast cancer, using data from 22 studies participating in the BCAC conducted in 12 countries.^40, The 22 studies included 30,056 controls. Data were reported on early death in 25,571 women, breast cancer-specific death in 24,345, and a diagnosis of second breast cancer in 25,094. Of the 25,571 women, 459 (1.8%) were CHEK2 c.1100delC heterozygous and 25,112 (98.2%) were noncarriers. Median follow-up was 6.6 years, over which time the following was observed: 124 (27%) early deaths occurred, 100 (22%) breast cancer-specific deaths occurred, and 40 (9%) second breast cancers among CHEK2 c.1100delC variant carriers were observed. Corresponding numbers among noncarriers were 4864 (19%), 2732 (11%), and 607 (2%), respectively. At the time of diagnosis, CHEK2-variant carriers versus noncarriers were on average 4 years younger (p<.001); additionally, CHEK2-variant carriers were more likely to have a family history of cancer (p<.001). Multifactorially adjusted HRs for CHEK2 versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; p=.004) for early death and 1.63 (95% CI, 1.24 to 2.15; p<.001) for breast cancer-specific death.

Section Summary: Clinically Valid

Studies have shown that a CHEK2 variant is of moderate penetrance and confers a risk of breast cancer 2 to 4 times that of the general population. This risk appears to be higher in patients who also have a strong family history of breast cancer. Although the CHEK2 variant appears to account for approximately one-third of variants identified in BRCA1- and BRCA2-negative patients, it is relatively rare with estimates ranging from 1.5% to 4.7% of breast cancer patients in the included studies, and risk estimates, which have been studied in population- and family-based case-controls, are subject to bias and overestimation. One systemic review and 2 studies published since the review estimated the risk of breast cancer by age 70 years in women with CHEK2 variants was close to 20%. However, another review estimated that it may be as high as 37% (95% CI, 26% to 56%) in women with familial breast cancer. Several studies have suggested that CHEK2 carriers with breast cancer may have worse breast cancer-specific survival and distant-recurrence-free survival, with about twice the risk of early death.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if individuals receive correct therapy, more effective therapy, or avoid unnecessary therapy or testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for individuals managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

Direct evidence of clinical utility for genetic testing in individuals with CHEK2 variants was not identified.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Weidner et al (2020) conducted a retrospective, consecutive study on 69 CHEK2 carriers enrolled in the Inherited CAncer REgistry (ICARE) at Vanderbilt University and their relatives.^41, Eligibility for annual breast magnetic resonance imaging surveillance was based on ≥20% lifetime risk of breast cancer based on family cancer history alone as calculated by the BOADICEA predictive model, or family cancer history and proband CHEK2 variant status, utilizing an updated version of the BOADICEA model (BWA v4). Among the CHEK2 carriers and family history alone, 21 first-degree relatives (FDRs) (14.9%) and 14 second-degree relatives (SDRs) (13.9%) had a lifetime cancer risk ≥20%. Inclusion of the proband's variant status significantly increased identification of FDRs to 78 (55.3%; p<.0001) and SDRs to 22 (21.8%; p=.008), respectively. While the study revealed that family history alone may be insufficient to appropriately identify at-risk FDRs and SDRs of CHEK2 carriers, the study authors note that the expanded BOADICEA predictive model (BWA v4) is not intended for clinical use.^42, Additionally, this version has not been licensed for commercial use. Additional study limitations include the retrospective study design, lack of clarity regarding to what extent study participants met society criteria for genetic testing for breast cancer risk, and no reporting of outcomes associated with enhanced screening for CHEK2 variant carriers.

For women with high-risk hereditary cancer syndromes, interventions to decrease breast cancer risk in high-risk women include screening (eg, starting at an early age, the addition of magnetic resonance imaging to mammography, and screening annually), chemoprevention, prophylactic mastectomy, and prophylactic oophorectomy. In contrast to high-penetrance variants, there is unlikely to be a similar benefit-to-risk calculus for preventive interventions in women with a CHEK2 variant. Surveys assessing adherence to guideline-based recommendations have explored this relationship but are limited in sample size and generally have not reported variant-stratified long-term outcomes of prophylactic or preventative interventions in controlled studies to support standard actionable thresholds for CHEK2.^43,7, Findings from other studies point to potential overtreatment through risk-reducing bilateral mastectomy among those with ATM/CHEK2 variants, with over half of all carriers reporting use of prophylactic surgery independent of family history or personal breast cancer history.^44,

Section Summary: CHEK2 and Breast Cancer Risk Assessment

Despite some studies showing potentially poorer outcomes for breast cancer patients who have CHEK2 variants, it is unclear how such knowledge would be used to alter the treatment of such a patient. Furthermore, updated predictive models utilizing information on CHEK2 status have not been approved for widespread clinical use. No evidence is available to support the clinical utility of genetic testing for CHEK2 variants in breast cancer patients to guide patient management. There is no strong chain of evidence supporting CHEK2 testing in breast cancer patients.

For individuals with risk of HBOC who receive genetic testing for a CHEK2 variant, the evidence includes studies of variant prevalence and studies of breast cancer risk. Relevant outcomes are OS, disease-specific survival, and test validity. The available studies on clinical validity have demonstrated that CHEK2 variants are of moderate penetrance, and confer a risk of breast cancer 2 to 4 times that of the general population. Direct evidence for the clinical utility of genetic testing for CHEK2 variants in individuals with risk of HBOC was not identified. It is unclear the RR associated with the moderate penetrance variants would increase risk enough beyond that already conferred by familial risk to change screening behavior. In contrast to high-penetrance variants, there is unlikely to be a similar benefit-to-risk calculus for risk-reducing mastectomy in women with a moderate penetrance variant such as CHEK2. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population reference No. 2

ATM and Breast Cancer Risk Assessment

Clinical Context and Test Purpose

The purpose of testing for ATM variants in individuals at high-risk of HBOC is to evaluate whether an abnormal variant is present and, if so, to determine whether the variant conveys a sufficiently high-risk that changes in surveillance and/or treatment likely to decrease the risk of mortality from breast and/or ovarian cancer are warranted.

The question addressed in this evidence review is: Does genetic testing for ATM variants improve the net health outcome in women at high-risk of HBOC?

The following PICO was used to select literature to inform this review.

Populations

Genetic testing can be considered for women at increased risk of developing hereditary breast cancer based on their family history or in women with breast cancer whose family history or cancer characteristics (eg, triple-negative disease, young age) increase the likelihood that the breast cancer is hereditary. Testing may also be considered for women from families with known variants.

The relevant population of interest in this review is patients who are undergoing assessment for HBOC syndrome.

Interventions

The intervention of interest is ATM variant testing.

Comparators

The alternative would be to manage women at high-risk of HBOC with no ATM genetic testing.

Outcomes

The outcomes of interest are OS, disease-specific (breast and ovarian cancer) survival, and test validity.

Study Selection Criteria

For the evaluation of the clinical validity of the tests, studies that meet the following eligibility criteria were considered:

• Included a suitable reference standard

• Patient/sample clinical characteristics were described with women at high breast cancer risk

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Systematic Reviews

A systematic review conducted by Moslemi et al (2021) included 24 cross-sectional studies reporting on the prevalence of ATM variants in individuals with breast cancer.^45, The review found a pooled prevalence of 7% (95% CI, 6% to 9%) based on 21 studies included in the meta-analysis with high heterogeneity (I²=93%). In individuals with an ATM and BRCA1 or BRCA2 mutation, prevalence was 11% (95% CI, 7% to 11%; I²=99%), in those with an ATM mutation but without a BRCA1/2 mutation, the prevalence was 3% (95% CI, 2% to 4%; I²=85%). Meta-regression found age did not have a significant effect on prevalence of ATM in individuals with breast cancer, and Egger's test did not reveal evidence of publication bias (p=.98).

The Suszynska et al (2019) systematic review described previously also included association estimates for ATM variants.^23, In the 43 breast cancer studies included in the review, 94,787 patients contributed to the meta-analysis of ATM in breast cancer patients. The OR of breast cancer for ATM variants was 2.42 (95% CI, 2.16 to 2.71). Given that the Suszynska et al (2019) report included only studies reporting on test results from a panel, it does not substantially overlap with the studies described in the following section including other ATM association studies.

Marabelli et al (2016) reported on a meta-analysis of the penetrance of ATM variants in breast cancer, which used a model allowing the integration of different types of cancer risk estimates to generate a single estimate associated with heterozygous ATM gene variants.^46, The meta-analysis included 19 studies, which were heterogeneous in terms of population, study designs, and baseline breast cancer risk. The estimated cumulative absolute risk of breast cancer in heterozygous ATM variant carriers was 6.02% by age 50 (95% credible interval, 4.58% to 7.42%) and 32.83% by age 80 (95% credible interval, 24.55% to 40.43%).

Association Studies

Individual studies published after the meta-analyses have also reported on the association between breast cancer development and pathogenic ATM variants. The study characteristics and limitations of Hu et al (2021), Southey et al (2021), Li et al (2021), Lu et al (2019), Hauke et al (2018), Kurian et al (2017), Decker et al (2017), and Couch et al (2017), were included in the previous section on CHEK2 (Tables 3, 5, and 6 ). Study results are shown in Table 7.

Table 7. Risk of Breast Cancer Associated with Pathogenic ATM Variants

BEACCON: Hereditary BrEAst Case CONtrol study; CI: confidence interval; OR: odds ratio; RR: relative risk.

Section Summary: Clinically Valid

ATM heterozygotes appear to have an RR of breast cancer about 2 to 3 times that of the general population, with an estimated absolute risk of 6% by age 50 and 33% by age 80. Estimates come from the population- and family-based case-controls, and are applicable to individuals at high risk of breast and/or ovarian cancer.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, more effective therapy, or avoid unnecessary therapy or testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

Direct evidence of clinical utility for genetic testing in individuals with ATM variants was not identified.

Weidner et al (2020) conducted a retrospective, consecutive study on 56 ATM carriers enrolled in the Inherited CAncer REgistry (ICARE) at Vanderbilt University and their relatives.^41, Eligibility for annual breast magnetic resonance imaging surveillance was based on ≥20% lifetime risk of breast cancer based on family cancer history alone as calculated by the BOADICEA predictive model, or family cancer history and proband CHEK2 variant status, utilizing an updated version of the BOADICEA model (BWA v4). Among the ATM carriers and family history alone, 24 FDRs (22.6%) and 15 SDRs (13.6%) had a lifetime cancer risk ≥20%. Inclusion of the proband's variant status significantly increased identification of FDRs to 60 (56.6%; p<.0001) and SDRs to 31 (28.1%; p<.0001), respectively. While the study revealed that family history alone may be insufficient to appropriately identify at-risk FDRs and SDRs of ATM carriers, the study authors note that the expanded BOADICEA predictive model (BWA v4) is not intended for clinical use.^42, Additionally, this version has not been licensed for commercial use. Additional study limitations include the retrospective study design, lack of clarity regarding to what extent study participants met society criteria for genetic testing for breast cancer risk, and no report of outcomes associated with enhanced screening for ATM variant carriers.

For women with high-risk hereditary cancer syndromes, interventions to decrease breast cancer risk in high-risk women include screening (eg, starting at an early age, the addition of magnetic resonance imaging to mammography, and screening annually), chemoprevention, prophylactic mastectomy, and prophylactic oophorectomy. In contrast to high penetrance variants, there is unlikely to be a similar benefit-to-risk calculus for preventive interventions in women with an ATM variant. Surveys assessing adherence to guideline-based recommendations have explored this relationship but are limited in sample size and generally have not reported variant-stratified long-term outcomes of prophylactic or preventative interventions in controlled studies to support standard actionable thresholds for ATM.^43,8, Findings from a study by Cragun et al (2020) point to potential overtreatment through risk-reducing bilateral mastectomy among those with ATM/CHEK2 variants, with over half of all carriers reporting use of prophylactic surgery independent of family history or personal breast cancer history.^44,

Section Summary: ATM and Breast Cancer Risk Assessment

Updated predictive models utilizing information on ATM status for enhanced screening have not been approved for widespread clinical use. No evidence is available to support the clinical utility of genetic testing for ATM variants in breast cancer patients to guide patient management, and there is no strong chain of evidence supporting ATM testing in breast cancer patients.

For individuals with risk of HBOC who receive genetic testing for an ATM variant, the evidence includes studies of variant prevalence and studies of breast cancer risk. Relevant outcomes are OS, disease-specific survival, and test validity. The available studies on clinical validity have demonstrated that ATM variants are of moderate penetrance ; moreover, ATM variants confer a risk of breast cancer 2 to 4 times that of the general population. Direct evidence for the clinical utility of genetic testing for ATM variants in individuals with risk of HBOC was not identified. It is unclear that the RR associated with the moderate penetrance variantswould increase risk enough beyond that already conferred by familial risk to change screening behavior. In contrast to high-penetrance variants, there is unlikely to be a similar benefit-to-risk calculus for preventive interventions in women with a moderate penetrance variant such as ATM. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 3 

BARD1 and Breast Cancer Risk Assessment

Clinical Context and Test Purpose

The purpose of testing for BARD1 variants in individuals at high-risk of HBOC is to evaluate whether an abnormal variant is present and, if so, to determine whether the variant conveys a sufficiently high-risk that changes in surveillance and/or treatment likely to decrease the risk of mortality from breast and/or ovarian cancer are warranted.

The question addressed in this evidence review is: Does genetic testing for BARD1 variants improve the net health outcome in women at high-risk of HBOC?

The following PICO was used to select literature to inform this review.

Populations

Genetic testing can be considered for women at increased risk of developing hereditary breast cancer based on their family history or in women with breast cancer whose family history or cancer characteristics (eg, triple-negative disease, young age) increase the likelihood that the breast cancer is hereditary. Testing may also be considered for women from families with known variants.

The relevant population of interest in this review is patients who are undergoing assessment for HBOC syndrome.

Interventions

The intervention of interest is BARD1 variant testing.

Comparators

The alternative would be to manage women at high-risk of HBOC with no BARD1 genetic testing.

Outcomes

The outcomes of interest are OS, disease-specific (breast and ovarian cancer) survival, and test validity.

Study Selection Criteria

For the evaluation of the clinical validity of the tests, studies that meet the following eligibility criteria were considered:

• Included a suitable reference standard

• Patient/sample clinical characteristics were described with women at high breast cancer risk

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Systematic Reviews

Two systematic reviews conducted by Suszynska et al in 2019^23, and 2020^47, reported estimates on the association of BARD1 variants with risk of breast cancer; study characteristics are summarized in Table 8. Prevalence of BARD1 mutations was 0.22% to 0.25% in individuals with breast cancer; prevalence in cases was about 0.09%. Study results appear in Table 9. The reviews found presence of a BARD1 mutation associated with approximately a 2 to 3-fold increased risk of breast cancer. The 2020 review identified 60 distinct pathogenic variants (PVs) among individuals with breast cancer, 21 of which were present in controls. In individuals with a recurrent PV (defined as occurring in 3 or more cases), risk was elevated among those with the c.334C>T (R112*), c.1652C>G (S551*), c.1690C>T (Q564*) PVs, but prevalence was very low (≤0.03% among cases and ≤0.004% among controls) and these estimates were imprecise.

Table 8. Characteristics of Systematic Reviews of BARD1 and Risk of Breast Cancer

NR: not reported; PV: pathogenic variant

Table 9. Results of Systematic Reviews of BARD1 and Risk of Breast Cancer

OR: odds ratio; PV: pathogenic variant; RR: relative risk

Association Studies

Individual studies not included in either of the meta-analyses have also reported on the association between breast cancer development and pathogenic BARD1 variants. The study characteristics and limitations of Hu et al (2021), Southey et al (2021), Li et al (2021), Couch et al (2017), and Kurian et al (2017) were described in the previous section on CHEK2 (Tables 3, 5, and 6). Study results are shown in Table 10. Although these studies found BARD1 associated with an elevated risk of breast cancer, the risk estimates were not statistically significant, potentially due to the low prevalence among controls.

Table 10. Risk of Breast Cancer Associated with Pathogenic BARD1 Variants

BEACCON: Hereditary BrEAst Case CONtrol study; CI: confidence interval; OR: odds ratio; RR: relative risk.

Section Summary: Clinically Valid

BARD1 heterozygotes appear to have an increased risk of breast cancer about 2 to 3 times that of the general population based on evidence from 2 systematic reviews that included a mix of population- and family-based controls. Presence of certain rare BARD1 PVs was associated with higher risk based on imprecise estimates. Evidence from individual studies not included in one of the reviews was generally consistent with that from the systematic reviews.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, more effective therapy, or avoid unnecessary therapy or testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

Direct evidence of clinical utility for genetic testing in individuals with BARD1 variants was not identified.

For women with high-risk hereditary cancer syndromes, interventions to decrease breast cancer risk in high-risk women include screening (eg, starting at an early age, the addition of magnetic resonance imaging to mammography, and screening annually), chemoprevention, prophylactic mastectomy, and prophylactic oophorectomy. In contrast to high-penetrance variants, there is unlikely to be a similar benefit-to-risk calculus for preventive interventions in women with a moderate penetrance BARD1 variant.

Section Summary: BARD1 and Breast Cancer Risk Assessment

No evidence is available to support the clinical utility of genetic testing for BARD1 variants in breast cancer patients to guide patient management, and there is no chain of evidence supporting BARD1 testing in breast cancer patients.

For individuals with risk of HBOC who receive genetic testing for a BARD1 variant, the evidence includes studies of variant prevalence and studies of breast cancer risk. Relevant outcomes are OS, disease-specific survival, and test validity. The available studies on clinical validity have demonstrated that BARD1 variants are of low to moderate penetrance; BARD1 variants confer a risk of breast cancer about 2 to 3 times that of the general population. Direct evidence for the clinical utility of genetic testing for BARD1 variants in individuals with risk of HBOC was not identified. It is unclear that the RR associated with the low to moderate penetrance variants would increase risk enough beyond that already conferred by familial risk to change screening behavior. In contrast to high-penetrance variants, there is unlikely to be a similar benefit-to-risk calculus for preventive interventions in women with a low to moderate penetrance variant such as BARD1. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Medical Genetics and Genomics

In 2023, the American College of Medical Genetics and Genomics published a practice resource on management of individuals with germline pathogenic/likely pathogenic variants in CHEK2.^48, The guidance document included the following relevant statements:

"For CHEK2 heterozygotes with truncating variants, ACMG advises the following:

• Personalized risk assessment using at least assessment of family history but ideally with a model such as CanRisk is important to consider when making BC surveillance recommendations.

• For women with BC, contralateral RRM should not routinely be offered but may be considered based on personalized risk assessment using a model such as CanRisk, the competing risk of first cancer prognosis, and shared medical decision making.

• For women without a prior diagnosis of breast cancer, bilateral risk-reducing mastectomy should not routinely be offered but may be considered based on a personalized risk assessment using a model such as CanRisk and shared medical decision making.

• Education on modifiable risk factors for cancer is undertaken."

"For CHEK2 heterozygotes with missense variants, ACMG advises the following:

• In general, risk and penetrance are reduced compared with CHEK2 truncating variants, and in isolation, they are unlikely to reach a level of clinical actionability,
  although some exceptions may exist, such as p.(Arg117Gly).

• Breast cancer, colorectal cancer, and prostate cancer surveillance should not be based on CHEK2 status but rather on personalized risk assessment, including family history and other risk factors, and joint decision making is encouraged.

• Education on modifiable risk factors for cancer is undertaken."

American College of Radiology

The American College of Radiology (ACR) has established Appropriateness Criteria^® for breast cancer screening (Table 11).^49, This includes high-risk women with a BRCA gene mutation and their untested first-degree relatives, women with a history of chest irradiation between 10 to 30 years of age, and women with 20% or greater lifetime risk of breast cancer as follows:

Table 11. American College of Radiology Appropriateness Criteria for Breast Cancer Screening in High-Risk Women

DBT: digital breast tomosynthesis; FDG-PEM: flurodeoxyglucose positron emission mammography; IV: intravenous; MBI: molecular breast imaging; MRI: magnetic resonance imaging; US: ultrasound. 

Specific recommendations for CHEK2, ATM, and BARD1 variant carriers are not available.

American Society of Breast Surgeons

A consensus guideline on genetic testing for hereditary breast cancer was updated in February 2019.^50, Guidelines state that genetic testing should be made available to all individuals with a personal history of breast cancer and that such testing should include BRCA1/BRCA2 and PALB2, with other genes as appropriate for the clinical scenario and patient family history. Furthermore, individuals who had previous genetic testing may benefit from updated testing. Finally, genetic testing should be made available to individuals without a personal history of breast cancer when they meet National Comprehensive Cancer Network (NCCN) guideline criteria. The guidelines also note that variants of uncertain significance are not clinically actionable.

For individuals with mutations in ATM and CHEK2, enhanced screening is recommended, however, the data are not sufficient to support risk-reducing mastectomy in the absence of other factors such as strong family history. For individuals with BARD1 mutations, evidence is insufficient to support change in breast cancer risk management based on the presence of a mutation alone.

American Society of Clinical Oncology and Society of Surgical Oncology

In 2024, the American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology published recommendations on germline genetic testing in individuals with breast cancer.^51, The recommendations included the following relevant statements:

"Recommendation 4.2. Testing for moderate penetrance breast cancer genes currently offers no benefits for treatment of the index breast cancer but may inform risks of second primary cancer or family risk assessment, and thus may be offered to appropriate patients who are undergoing BRCA1/2 testing (Type: Formal Consensus; Agreement: 87.50%)."

"Recommendation 4.3. If a multi-gene panel is ordered, the specific panel chosen should take into account the patient's personal and family history. Consultation with a provider experienced in clinical cancer genetics can be helpful in selecting a specific multi-gene panel or interpreting its results and should be made available to patients when possible (Type: Formal Consensus; Agreement: 91.43%)."

The document further states, "Other breast cancer susceptibility genes are often considered for testing. The particular genes included on breast cancer susceptibility gene panels varies between testing laboratories. Almost all include ATM, CHEK2, and PALB2. These genes do not currently have direct relevance for treatment of patients newly diagnosed with breast cancer as PARP inhibitors are not approved for treatment of individuals with germline PVs in any of these genes, and contralateral risks are modest at best. Affected women with PVs in these genes may be at sufficient risk to benefit from breast magnetic resonance imaging (MRI) screening and PALB2 is linked to an increased risk of ovarian cancer that may warrant post-menopausal salpingo-oophorectomy. The major benefit of testing for these genes, however, is to inform risk assessment of family members."^51,

Also in 2024, ASCO published a consensus guideline on the selection of germline genetic testing panels in individuals with cancer.^52, The document included a list of genes recommended for testing and inclusion in multigene panels. For breast cancer, the more strongly recommended genes (higher relative risk of cancer or highly actionable) were BRCA1, BRCA2, PALB2, CDH1, PTEN, STK11, and TP53. Less strongly recommended genes (moderate risk of cancer or potential impact for therapy/change in medical management) were ATM,BARD1,CHEK2,RAD51C,RAD51D, and NF1.

National Comprehensive Cancer Network

The NCCN (v.3. 2024) guidelines on genetic/familial high-risk assessment for breast and ovarian cancer review single-gene tests for CHEK2, ATM, and BARD1.^53, The guidelines state that for those that meet hereditary cancer testing criteria, testing for a specific familial pathogenic/likely pathogenic variant may be recommended for appropriate genes. For individuals who meet criteria with no known familial variants, comprehensive testing of a multigene panel may be considered. This testing may consider a number of genes, including but not limited to CHEK2, ATM, and BARD1. However, the inclusion of certain genes in the guideline does not imply the endorsement "for or against multigene testing for moderate-penetrance genes" and there are limited data on the degree of cancer risk associated with some genes in multigene panels. Testing an affected family member first has the highest likelihood of a positive result. The guidelines state that the panel recommends an annual mammogram for women with CHEK2, ATM, or BARD1 mutations beginning at age 40, with consideration of annual breast magnetic resonance imaging. The guidelines also state there is insufficient evidence to draw conclusions on risk-reducing mastectomy in individuals with CHEK2, ATM, or BARD1 mutations and that patients should be managed based on family history.

The NCCN guidelines on breast cancer screening and diagnosis ( v.2.2024)^54, recommend the following:

• Annual mammogram.

• Annual breast magnetic resonance imaging if the patient has >20% risk of breast cancer based on models largely dependent on family history.

• Consideration of risk-reducing strategies based on family history.

U.S. Preventive Services Task Force Recommendations

No U.S. Preventive Services Task Force recommendations for CHEK2, ATM, and BARD1 variant testing have been identified.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

An unpublished trial that might influence this review is listed in Table 12.

Table 12. Summary of Key Trials

NCT: national clinical trial.

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