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

POLICY NUMBER

A.2.04.126

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 the Germline Genetic Testing for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers (BRCA1, BRCA2, PALB2) medical policy.

Breast Cancer and Genetics

The National Cancer Institute estimated there would be 316,950 new cases of female breast cancer (FBC) and 2,800 cases of male breast cancer (MBC) diagnosed in 2025, with an expected 42,170 deaths due to FBC and 510 deaths due to MBC. 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. 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, 60% will develop breast cancer in their lifetime; risk in men with BRCA1 and BRCA2 variants is much lower (1% and 7%, respectively). Pathogenic variants in other highly penetrant genes (eg, TP53, CDH1, PTEN, STK11) contribute to a smaller number of cancer cases. CHEK2 and ATM are believed to be moderately penetrant, and BARD1 has alternatively been described as moderate, low/moderate, and low penetrance.

Testing for BRCA1, BRCA2, and PALB2 is addressed in the Germline Genetic Testing for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers (BRCA1, BRCA2, PALB2) medical policy.

Testing for mismatch repair genes linked to Lynch syndrome is addressed in the  Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes medical policy.

Testing for genes linked to Cowden/PTEN Hamartoma Tumor syndrome is addressed in the  Genetic Testing for PTEN Hamartoma Tumor Syndrome medical policy.

Testing for genes linked to Li-Fraumeni syndrome is addressed in the  Genetic Testing for Li-Fraumeni Syndrome medical policy.

Testing for genes linked to ovarian cancer (BRIP1, RAD51C, RAD51D, NBN) is addressed in the Molecular Testing for Germline Variants Associated with Ovarian Cancer (BRIP1, RAD51C, RAD51D, NBN) medical policy.

Penetrance of Pathogenic VariantsPenetrance 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). 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], and STK11 [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. 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 PathogenicityDetermining 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. The approach to defining pathogenicity is clearly outlined in standards and reporting guidelines. Still, distinctions between a variant of uncertain significance and a pathogenic one from different laboratories may not always be identical.

Genes Associated with a Moderate Penetrance of Breast Cancer

CHEK2 GeneThe 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.

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.

ATM GeneATM (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 GeneThe BARD1 (BRCA1-associated RING [Really Interesting New Gene] domain) gene is located on chromosome 2 (sequence 2q34-q35). BARD1 encodes a protein which 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. 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.

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. 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). 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). 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), screening tools (eg, BRCAPRO, Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, Family History Screen), or by referring to guidelines that define specific family history criteria. For women with breast cancer, family history also affects the likelihood of carrying a pathogenic variant.

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 and colleagues examined the agreement in variant classification by different laboratories from tests for inherited cancer susceptibility from individuals undergoing panel testing. 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.

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.

Related medical policies –

• Genetic Cancer Susceptibility Panels Using Next Generation Sequencing

POLICY

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

POLICY EXCEPTIONS

None 

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

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 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 the Germline Genetic Testing for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers (BRCA1, BRCA2, PALB2) medical policy.

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1). The Society's nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology- "pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"- to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA

 Table 2. American College of Medical Genetics and Genomics and the Association for Molecular Pathology Standards and Guidelines for Variant Classification

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.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

04/09/2015: Approved by Medical Policy Advisory Committee.

07/30/2015: Code Reference section updated for ICD-10.

03/09/2016: Policy description updated regarding the PALB2 gene. Policy statement unchanged. Policy guidelines updated to add genetic counseling information.

06/07/2016: Policy number A.2.04.126 added.

06/27/2017: Code Reference section updated to revise code description for CPT code 81406, effective 07/01/2017.

12/22/2017: Code Reference section updated to revise description for CPT code 81406 effective 01/01/2018.

04/09/2018: Policy title changed from "Genetic Testing for PALB2 Mutations" to "Moderate Penetrance Variants Associated with Breast Cancer in Individuals at High Breast Cancer Risk." Policy description re-written regarding breast cancer and genetics. Removed the following policy statement: Genetic testing for PALB2 mutations in patients with breast or pancreatic cancer or for cancer risk assessment in patients with or without a family history of breast or pancreatic cancer is considered investigational. Added statement that testing for PALB2 variants for breast cancer risk assessment may be considered medically necessary when meeting certain criteria. Added statement that testing for PALB2 sequence variants in individuals not meeting the criteria is investigational. Added statement that testing for CHEK2 and ATM variants in the assessment of breast cancer risk is considered investigational. Policy Guidelines updated regarding criteria for genetic risk evaluation and testing strategy. Code Reference section updated to change CPT code 81406 from investigational to covered and to add ICD-10 diagnosis codes C50.011 - C50.929 and Z80.3.

08/08/2018: Policy description updated regarding breast cancer risk. Policy statements unchanged. Policy Guidelines updated to remove the criteria for genetic risk evaluation of an individual with/without breast cancer and state that updated versions of the criteria are available on the NCCN website.

01/22/2019: Policy reviewed. Policy statements unchanged. Policy Guidelines updated regarding criteria for genetic risk evaluation.

08/13/2019: Policy description updated. Policy statements unchanged.

12/19/2019: Code Reference section updated to add new CPT codes 81307 and 81308 effective 01/01/2020. Removed CPT code 81406.

11/16/2020: Policy title changed from "Moderate Penetrance Variants Associated with Breast Cancer in Individuals at High Breast Cancer Risk" to "Gene Variants Associated with Breast Cancer in Individuals at High Breast Cancer Risk." Policy description updated to add links to related policies. Medically necessary criteria updated to remove the statement that the individual has undergone testing for sequence variants in BRCA1 and BRCA2 with negative results. Policy Guidelines updated to add the related policy where the recommended testing strategy can be found.

02/25/2022: Policy title changed from "Gene Variants Associated With Breast Cancer in Individuals at High Breast Cancer Risk" to "Gene Variants (PALB2, CHEK2 and ATM) Associated With Breast Cancer in Individuals at High Breast Cancer Risk." Policy description updated regarding breast cancer and genetics. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

04/01/2023: Policy title changed from "Gene Variants (PALB2, CHEK2 and ATM) Associated With Breast Cancer in Individuals at High Breast Cancer Risk" to "Germline Genetic Testing for Gene Variants Associated With Breast Cancer in Individuals at High Breast Cancer Risk (CHEK2, ATM, and BARD1)." Policy updated to remove information regarding PALB2 variants. Policy description updated regarding breast cancer and genetics, CHEK2 gene, BARD1 gene, individuals at risk of an inherited susceptibility to breast cancer, and variant interpretation. Policy statements for PALB2 testing moved to MP# A.2.04.02. Revised investigational statement to include BARD1. Policy Guidelines updated. Code Reference section updated to remove CPT codes 81307, 81308, and ICD-10 diagnosis codes. Added CPT codes 81408, 81479, 0102U, 0129U, and 0131U as investigational.

10/09/2023: Policy description updated regarding breast cancer and genetics. Policy statement unchanged.

09/11/2024: Policy reviewed; no changes.

09/17/2025: Policy description updated regarding new data for female breast cancer. Policy statement unchanged. Policy Guidelines updated regarding genetics nomenclature and variant classification.

SOURCE(S)

Blue Cross and Blue Shield Association Policy # 2.04.126

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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