Coverage Policy Manual
Policy #: 2015004
Category: Medicine
Initiated: January 2015
Last Review: September 2024
  Genetic Test: Germline Testing for Gene Variants Associated with Breast Cancer in Individuals at High Breast Cancer Risk (CHEK2, ATM and BARD1)

Description:
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 (NCI, 2023). 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 (NCI, 2022). 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) (NCI, 2022; ASCO, 2022). Pathogenic variants in other highly penetrant genes (e.g., TP53, CDH1, PTEN, STK11) contribute to a smaller number of cancers. CHEK2 and ATM are believed to be moderately penetrant and BARD1 has alternatively been described as moderate, low/moderate, and low penetrance (Sniadecki, 2020; Alenezi, 2020; Suszynska, 2019; Vysotskaia, 2020).
 
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 (greater than 50%), moderate (20% to 50%), and low (less than 20%) (corresponding relative risks of approximately greater than or equal to 5, 1.5 to 5, and less than 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], 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 (Easton, 2015). Penetrance can be modified by environmental factors and by family history, which is a particularly important modifier for low- and moderate-penetrance genes. In addition, specific pathogenic variants within a gene may confer somewhat different risks.
 
DETERMINING VARIANT PATHOGENICITY
Determining the pathogenicity of variants in a cancer-susceptibility gene most commonly detected (e.g., founder sequence variants) 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 (Richards, 2015). The approach to defining pathogenicity is clearly outlined in standards and reporting guidelines (Richards, 2015). Still, distinctions between a variant of uncertain significance and a pathogenic one from different laboratories may not always be identical (Kurian, 2016).
 
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 mutation 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 (Yadav, 2021).
 
Although most data for truncating CHEK2 variants are limited to the c.1100delC variant, 3 other founder variants of CHEK2 (IVS2+1G>A, del5395, I157T) have been associated with breast cancer in Eastern Europe. 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 (Cybulski, 2011).
 
ATM Gene
ATM (ataxia-telangiectasia [AT] mutated), located on chromosome 11q22.3, is associated with the autosomal recessive condition AT. 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, but 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 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 (Alenezi, 2020). BARD1 variants have been associated with an increased risk of estrogen-receptor (ER) negative breast cancer, triple-negative breast cancer, and with breast cancer at a younger age (under age 50 years) in some studies, but do not appear to increase risk of ovarian cancer (Sniadecki, 2020; Hu, 2021).
 
IDENTIFYING WOMEN AT RISK OF AN INHERITED SUSCEPTIBILITY TO BREAST CANCER
Breast cancer risk can be affected by genetic and nongenetic factors. 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 (Schottenfeld, 2006). A family history of breast cancer confers between a 2- and a 4- fold increased risk varying according to the number and closeness of affected relatives, age at which cancers developed, whether breast cancers were bilateral, and if other cancers occurred (e.g., ovarian) (Singletary, 2003). For a woman without breast cancer, the probability of detecting a pathogenic variant can be estimated from a detailed multigenerational pedigree (e.g., Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) (Antoniou, 2004), screening tools (e.g., BRCAPRO (Berry, 2002), Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, Family History Screen [Nelson, 2013; Nelson, 2014]), 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 (Antoniou, 2014).
 
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. Balmana et al examined the agreement in variant classification by different laboratories from tests for inherited cancer susceptibility from individuals undergoing panel testing (Balmana, 2016). 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 (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). CHEK2, ATM, and BARD1 testing are available under the auspices of CLIA. 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.
 
CODING
 
Testing for ATM variants is included in CPT Tier 2 molecular pathology code 81408: ATM (ataxia telangiectasia mutated) (e.g., ataxia telangiectasia), full gene sequence.
 
There is no specific CPT code for testing for CHEK2 variants. It is likely reported using the unlisted molecular pathology code 81479.
 
Related Policies
2001028: Magnetic Resonance Imaging (MRI), Breast
1998051: Genetic Testing for BRCA1, BRCA2 or PALB2 Mutations
2010014: Genetic Test: Cancer Susceptibility Panels Using Next Generation Sequencing
2004038: Genetic Test: Lynch Syndrome and Other Inherited Polyposis Syndromes
2004043: Genetic Test: Genetic Test: Melanoma Hereditary
2014013: Genetic Test: Li-Fraumeni Syndrome
2015009: Genetic Test: Next-Generation Sequencing for Cancer Susceptibility Panels and the Assessment of Measurable Residual Disease

Policy/
Coverage:
Effective June 15, 2023
 
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of this or another specific policy are met, limited genetic cancer susceptibility panels are covered, including only the gene variants for which a given member qualifies, as outlined in the policy.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Testing for CHEK2, ATM and BARD1 variants in the assessment of breast cancer risk does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, testing for CHEK2, ATM and BARD1 variants in the assessment of breast cancer risk is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective November 2020 through June 14, 2023
 
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of this or another specific policy are met, limited genetic cancer susceptibility panels are covered, including only the gene variants for which a given member qualifies, as outlined in the policy.
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Testing for PALB2 variants for breast cancer risk assessment in adults who meet the following criteria meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:
 
    • The individual meets criteria for genetic risk evaluation (as outlined above in "Description")  AND
    • The individual has undergone testing for sequence variants in BRCA1 and BRCA2 with negative results
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Testing for PALB2 sequence variants in individuals who do not meet the criteria outlined above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, testing for PALB2 sequence variants in individuals who do not meet the criteria outlined above is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.    
  
Testing for CHEK2 and ATM variants in the assessment of breast cancer risk does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, testing for CHEK2 and ATM variants in the assessment of breast cancer risk is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.   
 
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 does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, 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. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to November 2020
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Testing for PALB2 variants for breast cancer risk assessment in adults who meet the following criteria meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
1. The individual meets criteria for genetic risk evaluation (as outlined above in "Description")  AND
2. The individual has undergone testing for sequence variants in BRCA1 and BRCA2 with negative results
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Testing for PALB2 sequence variants in individuals who do not meet the criteria outlined above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, testing for PALB2 sequence variants in individuals who do not meet the criteria outlined above is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.    
  
Testing for CHEK2 and ATM variants in the assessment of breast cancer risk does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, testing for CHEK2 and ATM variants in the assessment of breast cancer risk is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.   
 
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 does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, 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. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
“Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com”
 
Literature that describes the analytic validity, clinical validity, and clinical utility of genetic testing for PALB2 mutations was sought.
 
Analytic Validity
Analytic validity is the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent.
 
Published data on the analytic validity of PALB2 mutation testing is lacking.
 
According to a large reference laboratory, analytic validity of testing detects 99% of described PALB2 gene sequence mutations (Myriad, 2014).
 
Clinical Validity
For genetic susceptibility to cancer, clinical validity can be considered, in part, on the following levels:
 
1. Does a positive test identify a person as having an increased risk of developing cancer?
 
2. If so, how high is the risk of cancer associated with a positive test?
 
The likelihood that someone with a positive test result will develop cancer is affected not only by the presence of the gene mutation, but also by other modifying factors that can affect the penetrance of the mutation (eg, environmental exposures, personal behaviors) or by the presence or absence of mutations in other genes.
 
Assessing the Prevalence of PALB2 Mutations in Patients With Hereditary Breast or Pancreatic Cancer
Fernandes et al sought to determine the prevalence of PALB2 mutations in patients with hereditary breast cancer (Fernandes, 2014).They performed comprehensive sequencing of PALB2 from 1479 patients who were referred, nonconsecutively, to a large, reference laboratory for genetic testing for hereditary breast and ovarian cancer syndrome (caused by a germline mutation in BRCA1 or BRCA2). All patients tested negative for BRCA mutations, both by Sanger sequencing and for large genomic rearrangements. The samples that were tested were stratified into 2 groups, based on the clinical history that was provided on the test requisition form. The “high-risk” group (n=955) consisted of samples from patients with breast cancer before age 50 years or male breast cancer at any age, and a family history of 2 or more diagnoses of breast cancer before age 50 or ovarian cancer at any age. The “lower-risk” group (n=524) consisted of samples from patients diagnosed with breast cancer whose personal and family history information did not meet criteria for inclusion into the high-risk group. Mutations identified by sequencing were classified as deleterious (disease causing), variant of unknown significance or a polymorphism. Deleterious mutations were identified in 12 of 1479 patients (0.81%). In the high-risk group, deleterious mutations were identified in 10 patients (1.05%; 95% confidence interval [CI], 0.5 to 1.92) and 2 in the lower-risk group (0.38%; 95% CI, 0.05 to 1.37). The difference in prevalence between the 2 risk groups was not statistically significant (p=0.14). Fifty seven PALB2 mutations of uncertain significance were identified among the 1479 patients (3.9%).
 
Casadei et al determined the prevalence of PALB2 mutations in 1144 familial breast cancer patients with negative BRCA mutation testing (Casadei, 2011).Thirty-three patients (2.9%) were found to have PALB2 mutations. Compared with their female relatives without PALB2 mutations, the increased risk of breast cancer was 2.3-fold (95% CI, 1.5 to 4.2) by age 55 and 3.4-fold (95% CI, 2.4 to 5.9) by age 85.
 
Ding et al determined the frequency of pathogenic BRCA2 mutations, followed by sequencing of the PALB2 gene in BRCA2-negative male breast cancer patients (Ding, 2011). BRCA2 mutations were identified in 18 of 115 patients; the difference in BRCA2 mutation frequencies between cases with and without a family history of breast cancer was not statistically significant. Of the 97 BRCA2-negative cases, 1 PALB2 mutation with confirmed pathogenicity and 1 mutation predicted to be pathogenic was identified, for a prevalence of pathogenic PALB2 mutations of 1% to 2%.
 
Stadler et al investigated the prevalence of PALB2 mutations in breast-pancreas cancer families (Stadler, 2011). Testing was performed in patients with either a personal history of both breast and pancreatic cancer or a personal history of breast cancer and a family history of a first-degree relative with pancreatic cancer. No PALB2 mutations were identified in 77 breast and pancreatic cancer families, including 22 probands with a personal history of both breast and pancreatic cancer.
 
Hofstatter et al studied whether PALB2 mutations were more prevalent in families with both breast and pancreatic cancers (Hofstatter, 2011). Eligible subjects were required to have a personal history of breast cancer and negative testing for BRCA1 and BRCA2 mutations. Other eligibility criteria included a family history of pancreatic cancer in first- or second-degree relatives or a personal history of pancreatic cancer. Of the 94 patients tested, 2 deleterious mutations were identified, for a prevalence of 2.1%.
 
Assessing the Risk of Developing Breast or Pancreatic Cancer in an Individual With a PALB2 Mutation
Antoniou et al studied the risk of breast cancer associated with inherited PALB2 mutations (Antoniou, 2014). The risk was analyzed among 362 members of 154 families who had deleterious mutations in PALB2; those with nondeleterious variants or variants of uncertain pathogenicity were excluded from the study. Families were identified through 14 research centers. Some families were ascertained through clinics for patients at high risk for breast cancer and others through screening of patients with breast cancer who were not selected on the basis of a positive family history.
 
Pedigree likelihoods were constructed with pedigree-analysis software. The 154 families included 311 women with PALB2 mutations, 229 of whom had breast cancer, and 51 men with PALB2 mutations, 7 of whom had breast cancer. Among the 154 families, 48 different loss-of-function PALB2 mutations were identified. The risk of breast cancer for carriers of a PALB2 mutation was increased by a factor of 9.47 (95% CI, 7.16 to 12.57) compared with the breast cancer incidence in the general population in the United Kingdom between the years of 1993 and 1997, using a single gene model of constant relative risk (RR) across all age groups. The cumulative risk of breast cancer for female PALB2 mutation carriers by age 50 years was 14% (95% CI, 9 to 20) and by 70 years, 35% (95% CI, 26 to 46). The absolute breast cancer risk for PALB2 female mutation carriers by age 70 years ranged from 33% (95% CI, 25 to 44) for those  
without a family history of breast cancer, to 58% (95% CI, 50 to 66) for those with a family history of breast cancer (defined as those with 2 or more first-degree relatives with breast cancer at 50 years of age). The RR of ovarian cancer among PALB2 mutation carriers was 2.3 (95% CI, 0.77 to 6.97; p=0.18). The RR of breast cancer for males with PALB2 mutations, compared with the male breast cancer incidence in the general population, was estimated to be 8.3 (95% CI, 0.77 to 88.5; p=0.08).
 
The risk estimates in this study are higher than those reported in other studies, suggesting a higher risk of breast cancer with a PALB2 mutation in an individual with a family history of breast cancer. The authors suggest that in certain populations, the breast cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers.
 
Zhang et al conducted a meta-analysis to estimate the relationship between PALB2 mutations and breast cancer risk (Zhang, 2013). They conducted a literature search through September 2013 and included 6 case-control studies with a total of 4499 breast cancer cases and 6369 healthy controls. Three studies were conducted in white populations and 3 in Asian populations. Depending on which genetic model was used for statistical analysis, the authors found that PALB2 mutations increased the risk of breast cancer, ranging from an odds ratio (OR) greater than 1.36 (95% CI, 1.20 to 1.52; p<0.001) to greater than 1.64 (95% CI, 1.42 to 1.91; p<0.001). Subgroup analysis by ethnicity showed that the risk was increased in both white and Asian populations.
 
Clinical Utility
Clinical utility refers to how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes.
 
Identifying a person with a genetic mutation that confers a high risk of developing cancer could lead to changes in clinical management and improved health outcomes. There are well-defined clinical guidelines on the management of patients who are identified as having a high-risk hereditary cancer syndrome. Changes in clinical management could include modifications in cancer surveillance, specific risk-reducing measures (eg, prophylactic surgery), and treatment guidance (eg, avoidance of certain exposures). In addition, other at-risk family members could be identified.
 
On the other hand, identifying mutations that have intermediate or low penetrance is of limited clinical utility. Clinical management guidelines for patients found to have one of these mutations are not well-defined. In addition, there is a potential for harm, in that the diagnosis of an intermediate- or low-risk mutation may lead to undue psychological stress and unnecessary prophylactic surgical intervention.
 
Published data on the clinical utility of testing for PALB2 mutations are lacking.
 
PALB2 mutations are rare in the general population, however, studies have estimated the prevalence of a PALB2 mutation in 1% to 3% of patients with hereditary breast cancer. PALB2 mutations are considered to be of intermediate penetrance, and carriers have approximately a 2- to 4-fold increased risk of developing breast cancer, when compared with the general population; these risk estimates may be higher in patients with a family history of breast cancer.
 
Population-based studies of breast cancer that have directly used family history data have indicated that at least some PALB2 mutations may be associated with breast cancer risk that is comparable with that of the average pathogenic BRCA2 mutation of 45% (95% confidence interval, 31% to 56%), however, these data are limited to few studies, and it is currently not known whether enhanced surveillance and/or preventative measures in patients with PALB2 mutations will lead to improved health outcomes.
 
There is insufficient evidence that screening individuals with a family history of pancreatic cancer improves survival, nor are there generally accepted clinical management guidelines for optimal screening modalities or intervals for screening for pancreatic cancer.
 
Published evidence on the clinical utility of testing for PALB2 mutations is lacking. Clinical management recommendations for inherited conditions associated with intermediate penetrance mutations, such as PALB2, are not standardized, nor is it known if testing for PALB2 mutations will lead to changes in patient management or improved health outcomes.
 
Practice Guidelines and Position Statements
In a 2010 policy statement update on genetic and genomic testing for cancer susceptibility, the American Society of Clinical Oncology (ASCO) stated that testing for high-penetrance mutations in appropriate populations has clinical utility in that they inform clinical decision making and facilitate the prevention or amelioration of adverse health outcomes but that genetic testing for intermediate-penetrance mutations are of uncertain clinical utility because the cancer risk associated with the mutation is generally too small to form an appropriate basis for clinical decision making (Robson, 2010). ASCO recommends that genetic tests with uncertain clinical utility (low-to-moderate penetrance mutations) be administered in the context of clinical trials.
 
National Comprehensive Cancer Network (NCCN) guidelines on genetic/familial high-risk assessment for breast and ovarian cancer (v1.2014) (NCCN, 2014) state that next generation sequencing gene panels for hereditary breast, ovarian and other cancers have limitations including an unknown percentage of variants of unknown significance, uncertainty of level of risk associated with most of the genes on the panel, and lack of clear guidelines on the risk management of carriers of some of the mutations on the panel. The guidelines also state, “Because of the complexity and limited data regarding their clinical utility, hereditary multigene cancer panels should only be ordered in consultation with a cancer genetics professional.”
 
NCCN guidelines for pancreatic cancer do not address the use of testing for PALB2 mutations.
 
A multidisciplinary consortium, the International Cancer of the Pancreas Screening consortium, met to discuss pancreatic screening and vote on statements. A consensus was considered reached if 75% or more agreed or disagreed. There was excellent agreement that, to be successful, a screening program should detect and treat T1N0M0 margin-negative pancreatic cancers and high-grade dysplastic precursor lesions. It was agreed that the following were candidates for screening: first-degree relatives of patients with pancreatic cancer from a familial pancreatic cancer kindred with at least 2 affected first-degree relatives; patients with Peutz-Jeghers syndrome; and p16, BRCA2, and hereditary non-polyposis colorectal cancer mutation carriers with 1 or more affected first-degree relative (Canto, 2013).
 
2016 Update
A literature search conducted through January 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Judkins and colleagues (2015) reported analytic sensitivity exceeding 99.9% (Sanger sequencing referent) for all genes in a 25 gene panel which includes PALB2 (Judkins, 2015).
 
Jones and colleagues examined 96 patients with familial pancreatic cancer for germline PALB2 mutations (Jones, 2009). Protein truncating PALB2 variants were identified in 3 patients (3.1%). Slater and colleagues evaluated probands from 81 European familial pancreatic cancer families and identified 3 protein truncating PALB2 variants (3.7%) (Slater, 2010).
 
In patients with familial breast cancer, others have reported mutation prevalence within a similar range (Nguyen, 2015). For In addition, founder mutations have been identified—eg, among women of Finnish (Erkko, 2008), Canadian (Foulkes, 2007), Polish (Cybulski, 2015), and Australian (Southey, 2010) descent.
 
Assessing the Risk of Developing Breast Cancer in an Individual With a PALB2 Mutation
A number of studies have examined relative and absolute risks of breast cancer in women with PALB2 mutations. All but 2 (Antoniou 2014 and Cybulski 2015) were limited by small numbers of affected cases. Estimated risks varied according to specific mutations, age, and family histories. A 2015 metaanalysis included 13 studies of protein-truncating variants where odds ratios were either reported or Calculable (Aloraifi, 2015).  Relevant studies not included in that analysis are summarized separately.
 
Erkko and colleagues studied PALB2 mutations in 1918 Finnish women with breast cancer (Erkko, 2008). Seventeen PALB2 c.1592delT probands were examined; 10 (mean age onset, 54.3 years) had a family history of breast cancer and 7 did not (mean age onset, 59.3 years). The RR of breast cancer conferred by the mutation was 14.3 (95% CI, 6.6 to 31.2) but decreased with increasing age. The estimated cumulative risk of breast cancer at age 70 years was 40% (95% CI, 17 to 77). Although the small number of women with c.1592delT mutations resulted in substantial uncertainty in the point estimates, the results are consistent with at least moderate penetrance.
 
Southey and colleagues evaluated 1403 Australasian women with invasive breast cancer not selected based on family history (Southey, 2010). From a model assuming Hardy-Weinberg equilibrium, a dominant action of PALB2 c.3113 G > A, and other influences on breast cancer risk, 5 population-based mutation carrier families had a HR of 30.1 (95% CI, 7.5 to 120) for developing breast cancer. The cumulative risk to age 50 was estimated at 49% (95% CI, 15 to 93), and 91% (95% CI, 44 to 100) by age 70. Although the estimates consistent increased breast cancer risk, implications are limited by the large uncertainty as reflected in the confidence intervals.
 
Easton and colleagues in a review of panel testing pooled relative risks from 4 case-control and family studies including Antoniou et al. Methods were not detailed but they estimated a PALB2 mutation to confer a RR of 5.3 (95% CI, 3.0 to 9.4) (Easton, 2015).
 
Thompson and colleagues evaluated 1996 Australian women with breast cancer referred for genetic evaluation and 1998 controls (Thompson, 2015). Nineteen protein truncating variants were identified—26 in cases (1.3%) and 4 in controls (0.2%) with a relative odds for breast cancer of 6.58 (95% CI, 2.3 to 18.9). In addition, many missense variants identified were slightly more common in cases (OR 1.15; 95% CI, 1.02 to 1.32).
 
Cybulski and colleagues examined 2 loss-of-function PALB2 mutations (509_510delGA and 172_175delTTGT) in women with invasive breast cancer diagnosed between 1996 and 2012 in Poland (Cybulski, 2015). From 12,529 women genotyped a PALB2 mutation was identified in 116 (0.93%; 95% CI, 0.76 to 1.09) versus 10 of 4702 controls (0.21%; 95% CI, 0.08 to 0.34); OR for breast cancer of 4.39 (95% CI, 2.30 to 8.37). In contrast, a BRCA1 mutation was identified in 3.47% of women with breast cancer and 0.47% of controls (OR=7.65; 95% CI, 4.98 to 11.75). The authors estimated a PALB2 mutation conferred a 24% cumulative risk of breast cancer by age 75 (in the a setting of age-adjusted breast cancer rates that are slightly over half that in the United Kingdom (Antoniou, 2015)  or the United States [http://seer.cancer.gov/statfacts/html/breast.html]). A PALB2 mutation was also associated with poorer prognosis—a 10-year survival of 48.0% versus 74.7% and a HR adjusted for prognostic factors of 2.27 (95% CI, 1.64 to 3.15) for death.
 
 Aloraifi and colleagues conducted a meta-analysis of studies reporting genotyped cases along with controls in women with protein-truncating variants including those in PALB2 (Aloraifi, 2015).  Studies of women with early onset breast cancer (<50 years of age), presence of a family history, or bilateral breast cancers were identified (PubMed search through June 1, 2014). Studies of sporadic or male breast cancers were excluded. Thirteen studies of PALB2 protein-truncating variants were included—5862 cases (91 with PALB2 variants) and 17,453 controls (9 with PALB2 variants). Studies were conducted in a variety of different ethnic groups. The authors reported a pooled OR for breast cancer of 21.40 (95 CI, 10.10 to 45.32). However, in 9 studies no controls were identified with a variant or effectively “0 events” in the control group contributing the large magnitude of effect and wide confidence interval. Sensitivity analyses, of particular relevance given the unstable estimates, were not reported. The estimate reported is also substantially larger than that reported by either Cybulski and colleagues or Antoniou and colleagues
.
Estimated absolute and relative risk varied across studies, but the magnitudes are consistent with increased breast cancer risk conferred by protein-truncating PALB2 variants. But given the low prevalence of mutations, the overall number of women studied with protein-truncating PALB2 variants is not large—approximately 500 with breast cancer and 105 without. Only 2 studies included over 40 women with breast cancer and PALB2 mutations. Additionally, with few exceptions (eg, c.1592del and c.3113d) specific variants were uncommon. The magnitude of increased risk for pancreatic cancer is unclear.
 
The body of evidence is consistent with protein-truncating PALB2 variants conferring increased absolute and relative risks for breast cancer. In some studies, the magnitudes of estimated risk exceed those that could change management—for example, screening asymptomatic carriers (eg, with lifetime risk >20%) with MRI and clinical exam. However, the number of additional women recommended to undergo screening based on PALB2 testing, over and above based on family history alone is unclear. Furthermore, PALB2 results have not been incorporated into standard risk models. Whether the increased risk warrants considering risk reduction mastectomy requires a high level of certainty; the existing body of evidence does not yet provide that level of certainty. Furthermore, given that many mutations are rare, the basis for determining pathogenicity (ie, whether the variant is protein-truncating) may be limited requiring considerable genetic expertise.
 
Protein truncation PALB2 variants appear to be responsible for some cases of familial pancreatic cancers, but the proportion is uncertain. Whether screening asymptomatic high-risk patients can improve
health outcomes is unclear (Canto, 2006;L langer, 2009; Harinck, 2015) a consensus recommendation from International Cancer of the Pancreas Screening consortium concluded “PALB2 mutation carriers with one or more affected FDR [first degree relative] with PC [pancreatic cancer] should be screened (agree 77.5%, grade very low, ‘probably do it’).”
 
The evidence for genetic testing for a protein-truncating PALB2 mutation in individuals who have cancer or a family history of cancer and criteria that would suggest a possibility of HBOC includes studies of analytic validity, mutation prevalence, and multiple studies of breast cancer risk including 1 meta-analysis. Relevant outcomes are overall survival, disease-specific survival, as well as test accuracy and validity. Reported accuracy of the test has been high. Estimated absolute and relative risk for breast cancer varied across studies, but the magnitudes are consistent with increases conferred by protein-truncating PALB2 variants. But given the low prevalence of variants, the overall number of women studied with protein-truncating PALB2 variants is not large. Additionally, with few exceptions specific variants are uncommon. Whether PALB2 testing would result in management changes that would not occur based on family history alone is unclear. Whether the increased risk warrants considering risk reduction mastectomy requires a high level of certainty; the existing body of evidence does not yet provide that level of certainty.
 
The evidence is insufficient to determine the effects of the technology on health outcomes. The evidence for genetic testing for a protein-truncating PALB2 variant in individuals who have a family history of pancreatic cancer includes studies of prevalence in patients with familial pancreatic cancer. Relevant outcomes are overall survival, disease-specific survival, as well as test accuracy and validity. Protein truncation PALB2 variants appear responsible for some cases of familial pancreatic cancers, but the proportion is unclear. Whether screening asymptomatic high-risk patients can improve health outcomes is uncertain. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
2017 Update
A literature search conducted through February 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Analytic validity is the accuracy of a test for detecting a variant that is present or not detecting a variant that is absent. Assuming testing is performed using next-generation sequencing (NGS) methods, techniques used have generally high analytic accuracy for variant identification. However, NGS platforms differ in terms of the depth of sequence coverage, methods for base calling and read alignment, and other factors. NGS sequencing accuracy can vary by genomic region and affected by region complexity (Goldfeder, 2016). These factors contribute to variability across the platforms and procedures used by different clinical laboratories. The American College of Medical Genetics and Genomics has clinical laboratory standards for NGS (Rehm, 2013). The guidelines outline the documentation of test performance measures that should be evaluated for NGS platforms, and note that typical definitions of analytic sensitivity and specificity do not apply for NGS. Verification of detected sequence variants by Sanger sequencing is generally standard practice and conclusions of a recent study suggests it may be required for hereditary cancer testing (Mu, 2016). Mu and colleagues (2016) examined results from 20,000 hereditary cancer NGS panels (including PALB2) and found an overall 1.3% false-positive NGS rate (0.66% for PALB2) compared with Sanger sequencing. Other published results specific to PALB2 testing are limited. According to a large reference laboratory, the analytic validity of NGS testing detects 99% of described PALB2 gene sequence variants (BCBSA TEC, 1997). Judkins and colleagues (2015) reported analytic sensitivity exceeding 99.9% (Sanger sequencing referent) for all genes in a 25-gene panel that includes PALB2 and CHEK2 (Judkins, 2015).
 
PALB2 AND BREAST CANCER RISK ASSESSMENT
Individual Clinical Validity Studies: Breast Cancer
Nine studies reporting relative risks or odds ratios (ORs) were included (2 reported penetrance estimates) (Antoniou, 2014; Catucci, 2014; Casadei, 2011; Cybulski, 2015; Erkko, 2008; Heikkinen, 2009; Rahman, 2007; Thompson, 2015; Southey, 2016). Study designs included family segregation (Erkko, 2008), kin-cohort (Antoniou, 2014), family-based case-control (Casadei, 2011; Rahman, 2007), and population-based or multicenter case-control (Catucci, 2014; Cybulski, 2015; Heikkinen, 2009; Thompson, 2015; Southey, 2016). The 2 multinational studies included individuals from up to 5 of the single country studies (Antoniou, 2014; Southey, 2016). The number of pathogenic variants identified varied from 1 (founder variants examined) to 48. Studies conducted from single country samples are described first followed by the 2 multinational collaborative efforts. Finally, pooled results are reported minimizing any overlap of samples.
 
Rahman and colleagues (2007) conducted a family-based case-control study enrolling cases (mean age, 49 years) identified at U.K. Cancer Genetics clinics (Rahman, 2007). Controls, aged 48 years living in geographic regions similar to cases, were selected from the 1958 Birth Cohort Collection study. Variants were identified by Sanger sequencing, with a detection rate of 90% assumed for analysis. Protein-truncating PALB2 variants were identified in 10 of 923 individuals with a family history of breast cancer but none in 1084 controls. In a segregation analysis, the relative risk of breast cancer associated with a PALB2 variant was 2.3 (95% CI, 1.4 to 3.9), but modified by age with a relative risk of 3.0 for women less than 50 years (95% CI, 1.4 to 3.9) and 1.9 (95% CI, 0.8 to 3.7) for women over 50 years. In addition, 50 non-protein-truncating variants were identified without evidence for increasing breast cancer risk. This study, likely the first to report an association between PALB2 and breast cancer, was limited by its sample size and possibly analytic sensitivity of the sequencing employed. Casadei and colleagues (2011) studied 959 U.S. women (non-Ashkenazi Jewish descent) with a family history of BRCA1- or BRCA2-negative breast cancer and 83 female relatives using a familybased case-control design (Casadei, 2011). Using conventional sequencing, pathogenic PALB2 variants were detected in 31 (3.2%) women with breast cancer and none in controls. Compared with their female relatives without PALB2 variants, the risk of breast cancer increased 2.3-fold (95% CI,1.5 to 4.2) by age 55 and 3.4-fold (95% CI, 2.4 to 5.9) by age 85. Mean age at diagnosis was not associated with the presence of a variant (50.0 years with vs 50.2 years without). The study reported a lower relative risk estimate than all but Rahman and colleagues and provided few details of analyses, and the prevalence of pathogenic PALB2 variants in women with breast cancer was higher than in all but 1 other study (Rahman, 2007). Additionally, participants reported over 30 ancestries and, given intermarriage in the U.S. population stratification may have had an impact on results. Generalizability of the relative risk estimate is therefore unclear.
 
Heikkinen and colleagues conducted a population-based case-control study at a Finnish university hospital employing 2 case groups (947 familial and 1274 sporadic breast cancers) and 1079 controls (Heikkinen, 2009). The study sample was obtained from 542 patients with familial breast cancer, a series of 884 oncology patients (79% of consecutive new cases), and 986 surgical patients (87% of consecutive new cases); 1706 were genotyped for the PALB2 c.1592delT variant. All familial cases were BRCA1- and BRCA2-negative, but among controls were 183 BRCA carriers. PALB2 variant prevalence varied with family history¾2.6% when 3 or more family members were affected and 0.7% in all breast cancer patients. Variant prevalence was 0.2% among controls. In women with hereditary disease, a PALB2 c.1592delT variant was associated with an increased risk of breast cancer (OR= 11.0; 95% CI, 2.65 to 97.78), and was higher in women with the strongest family histories (women with sporadic cancers OR=4.19; 95% CI, 1.52 to 12.09). Although data were limited, survival was lower among PALB2-associated cases (10-year survival, 66.5% [95% CI, 44.0% to 89.0%] vs 84.2% [95% CI, 83.1% to 87.1%] in women without a variant, p=0.041; hazard ratio [HR], 2.94, p=0.047). A PALB2 variant was also associated with triple-negative tumors—54.5% versus 12.2% with familial disease and 9.4% in sporadic cancers. The study was large as required for a population-based design. The magnitude of the odds ratio for women with family histories was substantial, but accompanied by substantial uncertainty (wide confidence interval).
 
Catucci and colleagues performed population-based case-control studies in Italy (Milan or Bergamo) among women at risk for hereditary breast cancer and no BRCA1 or BRCA2 variant (Catucci, 2014). In Milan, 9 different pathogenic PALB2 variants were detected in 12 of 575 cases and none in 784 controls (blood donor); in Bergamo PALB2 c.1027C>T variants were detected in 6 of 113 cases and in 2 of 477 controls (OR=13.4; 95% CI, 2.7 to 67.4). Performed in 2 distinct populations, the combined sample size was small and uncertainty in the effect estimate large.
 
Thompson and colleagues evaluated Australian women with breast cancer (n=1996) referred for genetic evaluation from 1997 to 2014 (Thompson, 2015). A control group was accrued from participants in the LifePool study (n=1998) who were recruited for a mammography screening program. All PALB2 coding exons were sequenced by NGS and novel variants verified by Sanger sequencing. Large deletions or rearrangements were not evaluated. Five bioinformatics computational tools were used to assess pathogenicity of novel variants. Nineteen distinct pathogenic variants were identified, including 6 not previously described—in 26 (1.3%) cases and in 4 (0.2%) controls—with an odds ratio for breast cancer of 6.58 (95% CI, 2.3 to 18.9). In addition, 54 missense variants identified were slightly more common in cases (OR=1.15; 95% CI, 1.02 to 1.32). This large population-based case-control study used contemporary NGS methods and informatics approaches. The reported odds ratio is consistent with other studies examining multiple pathogenic variants.
 
Cybulski and colleagues (2015) examined 2 loss-of-function PALB2 variants (c.509_510delGA, c.172_175delTTGT) in women with invasive breast cancer diagnosed between 1996 and 2012 in Poland (Cybulski, 2015). From 12,529 genotyped women, a PALB2 variant was identified in 116 (0.93%) cases (95% CI, 0.76% to 1.09%) versus 10 (0.21%, 95% CI, 0.08% to 0.34%) of 4702 controls (OR= 4.39; 95% CI, 2.30 to 8.37). A BRCA1 variant was identified in 3.47% of women with breast cancer and in 0.47% of controls (OR=7.65; 95% CI: 4.98 to 11.75). Authors estimated that a PALB2 sequence variant conferred a 24% cumulative risk of breast cancer by age 75 (in the setting of age adjusted breast cancer rates slightly more than half that in the U.K. (Antoniou, 2015) or the U.S. [seer.cancer.gov]). A PALB2 variant was also associated with a poorer prognosis—10-year survival of 48.0% versus 74.7% when the variant was absent (HR=2.27; 95% CI, 1.64 to 3.15; adjusted for prognostic factors). This population-based case-control study was largest and the relative risk estimate in the lower range of study estimates.
 
Antoniou and colleagues (2014) analyzed data from 362 members of 154 families with deleterious PALB2 variants. Individuals with benign variants or variants of uncertain significance (VUS) were excluded. Families were recruited at 14 centers in 8 countries (U.S., U.K., Finland, Greece, Australia, Canada, Belgium, Italy) and had at least 1 member with a BRCA1- or BRCA2-negative PALB2-positive breast cancer. There were 311 women with PALB2 variants—229 had breast cancer; 51 men also had PALB2 variants (7 had breast cancer). Of the 48 pathogenic (loss-of-function) variants identified, 2 were most common (c.1592delT in 44 families, c.3113G>A in 25 families); 39 of the 48 pathogenic variants were found in just 1 or 2 families.
 
Carriers of PALB2 variants (men and women) had a 9.47-fold increased risk for breast cancer (95%
CI, 7.16 to 12.57) compared with the U.K. population under a single-gene model and age-constant relative risk; 30% of tumors were triple negative. For a woman ages 50 to 54, the estimated relative risk was 6.55 (95% CI, 4.60 to 9.18). The relative risk of breast cancer for males with PALB2 variants, compared with the male breast cancer incidence in the general population, was 8.3 (95% CI, 0.77 to 88.5; p=0.08). The cumulative risk at age 50 of breast cancer for female PALB2 carriers without considering family history was 14% (95% CI, 9% to 20%); by age 70, it was 35% (95% CI, 26% to 46%). A family history of breast cancer increased the cumulative risk: if a woman with a PALB2 variant has a sister and mother who had breast cancer at age 50, by age 50 she would have a 27% (95% CI, 21% to 33%) estimate risk of developing breast cancer; and by age 70, a 58% (95% CI, 50% to 66%) risk. These results emphasize that family history affects penetrance. Authors noted that the study “includes most of the reported families with PALB2 variant carriers, as well as many not previously reported....” Still, the number of individuals with PALB2 variants and breast cancer was not large and many variants were examined.
 
Southey and colleagues (2016) examined the association of 3 PALB2 variants (2 protein truncating: c.1592delT and c.3113G>A; 1 missense c.2816T>G) with breast, prostate, and ovarian cancers (Southey, 2016). The association with breast cancer was examined among participants in the Breast Cancer Association Consortium (BCAC; 42,671 cases and 42,164 controls). BCAC (part of the larger Collaborative Oncological Gene-environment Study) included 48 separate studies with participants of multiple ethnicities, but mainly European, Asian, and African American. Most studies were population or hospital-based case control with some oversampling cases with family histories or bilateral disease. A custom array was used for genotyping at 4 centers, with 2% duplicate samples. Odds ratios were estimated adjusting for study among all participants, and excluding those studies selecting patients based on family history or bilateral disease (37,039 cases and 38,260 controls). The c.1592delT variant was identified in 35 cases and 6 controls (from 4 studies in the U.K., Australia, U.S., Canada; OR=4.52; 95% CI, 1.90 to 10.8; p<0.001); in those with no family history or bilateral disease (OR=3.44; 95% CI, 1.39 to 8.52; p=.003). The c3113G>A variant was identified in 44 cases and 8 controls (9 studies from Finland and Sweden; OR=5.93; 95% CI, 2.77 to 12.7; p<0.001) and in those with no family history or bilateral disease (OR=4.21; 95% CI, 1.84 to 9.60; p<.001). There was no association between the c2816T>G missense variant and breast cancer (found in 150 cases and 145 controls).
 
These results derived from a large sample, used a different analytical approach than Antoniou and colleagues, and examined only 2 pathogenic variants. The magnitude of the estimated relative risks approaches that of a high penetrance gene, but is accompanied by wide confidence intervals owing the study design and low carrier prevalence. The lower estimates obtained following exclusion of those selected based on family history or bilateral disease are consistent with the importance of carefully considering risk of hereditary disease prior to genetic testing.
 
Variant Interpretation
Valid variant classification is required to assess penetrance and is of particular concern for low prevalence variants including PALB2. Although the more common founder variants were identified in many patients in the clinical validity studies, some specific variants were infrequent in the samples. While there are guidelines for variant classification, the consistency of interpretation is among laboratories is of interest. Balmaña and colleagues (2016) examined agreement of variant classification by different laboratories from tests for inherited cancer susceptibility from individuals undergoing panel testing (Balmana, 2016). The Prospective Registry of Multiplex Testing (PROMPT) registry is a volunteer sample of patients who were 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. Of 49 missense PALB2 results with multiple interpretations, 9 (18%) had at least 1 conflicting interpretation—3 (6%) had pathogenic, VUS, or likely benign interpretations from different sources. Given the nature of the sample, there was a significant potential for biased selection of women with either a reported VUS 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.
 
Section Summary: Clinical Validity
The overall number of women with breast cancer and PALB2 variants included in these studies is modest owing to the low carrier rates and is consistent with the penetrance estimates. Identified studies differed in populations, designs, sample sizes, analyses, and variants examined. While relative risk estimates varied across studies, their magnitudes are at least moderate and approach the range for a highly penetrant variant.
 
Errors in missense variant classification have been reported. False negatives would result in risk determined by family history alone or may offer incorrect reassurance; the consequences of false positives may have adverse consequences due to incorrect management decisions. Finally, of interest is how variant detection affects penetrance estimates compared with family history alone. As with BRCA variants, model-based estimates allow estimating risks for individual patient and family characteristics. To illustrate using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm model, a woman age 30 whose mother had breast cancer at age 35 has an estimated 14.4% risk of breast cancer at age 70; if she carries a PALB2 variant, the risk increases to 51.1%. A woman age 50 with breast cancer whose mother had breast cancer at age 50, has an estimated 11.7% risk of a contralateral cancer by age 70, increasing to 28.7% if she carries a PALB2 variant.
 
Clinical Utility
Evidence of clinical utility limited to women with PALB2 variants was not identified. Studies of women at high risk based on family history alone or in those with BRCA1 and BRCA2 variants were reviewed given the penetrance estimates for PALB2 and related molecular mechanism (“BRCA-ness”). Interventions to decrease breast cancer risk in asymptomatic high-risk women include screening (eg, starting at an early age, addition of magnetic resonance imaging [MRI] to mammography, and annually), chemoprevention, prophylactic mastectomy, and prophylactic oophorectomy. In women with breast cancer, contralateral prophylactic mastectomy (CPM) is of interest; other treatment decisions are dictated by clinical, pathologic, and other prognostic factors. A concise review of evidence for these interventions follows and all are addressed in guidelines. Lifestyle modifications including weight loss, exercise, limiting alcohol consumption, and avoiding long-term hormone therapy are also recommended, but evidence demonstrating efficacy is indirect and based on observational studies.
 
Screening High-Risk Women
In addition to mammography, annual MRI screening is recommended beginning at an early age for asymptomatic women at high risk (eg, by National Comprehensive Cancer Network [NCCN] at age 25
(NCCN, V2.2016) when the lifetime breast cancer risk exceeds 20%, by the National Institute for
Health and Care Excellence at age 30 in women with a known BRCA1 or BRCA2 variant or with >30% risk of being a carrier [nice, 2015]) (Lee, 2010). We identified a recent meta-analysis of screening MRI in BRCA1 and BRCA2 carriers, 2 systematic reviews, and an observational study examining survival.
 
Phi and colleagues (2016) compared performance characteristics of MRI with mammography or the 2 modalities combined in an individual patient data meta-analysis of 6 high-risk screening trials (Phi, 2016). Among 1219 women with BRCA1 and 732 with BRCA2 variants, the sensitivity of MRI was better than mammography, but increased false positives by 8 to 10 per 100 screens.
 
A 2014 review supported by the Australia Medical Services Advisory Committee provided similar conclusions (Seil, 2014): “MRI offers a 2.3-fold increase in the detection of breast cancer in younger high-risk women over mammography alone.” “Breast MRI increases by 3-fold the rate of investigations for false-positive findings.” In addition, evidence for a favorable stage shift with MRI screening was noted.
 
A prospective matched-cohort study, the MRI Screening Study (MRISC), enrolling 2308 participants, found adding annual MRI to mammography improved metastasis-free survival in BRCA1 carriers
(HR=0.30; 95% CI, 0.08 to 1.13; p=0.055) and in women with a family history of breast cancer (HR=
0.21; 95% CI, 0.04 to 0.95; p=0.024) (Saadatmand, 2015). No benefit was observed in BRCA2 carriers. The study was limited by its observational design and small subgroups. The 2014 U.S. Preventive Services Task Force (USPSTF) report on testing for BRCA-related cancer noted a lack of randomized controlled screening trials in women with BRCA variants (Nelson, 2013; Nelson, 2014). The evidence is consistent that MRI screening in a high-risk population can identify more breast cancers than mammography with an increase in false positives. Indirect evidence and limited observational data suggest potential benefit from MRI screening.
 
Chemoprevention
Guidelines consider risk-reducing agents appropriate for women at risk of hereditary breast cancer. For example, NCCN recommends tamoxifen, raloxifene, anastrozole, and exemestane as potential options in women 35 years or older (NCCN, V.2.2016). The 2014 USPSTF BRCA review failed to identify trials limited to BRCA carriers, but concluded that tamoxifen and raloxifene decreased invasive breast cancer incidence compared with placebo (by 30% and 68%, respectively) (Nelson, 2013; Nelson, 2014). Phillips and colleagues (2013) pooled results from 3 observational chemoprevention studies of BRCA1 (n=1583) and BRCA2 (n=881) carriers with breast cancer (Phillips, 2013). Women receiving tamoxifen following an initial breast cancer diagnosis had a decreased risk of contralateral breast cancer (in BRCA1 carriers: HR=0.58; 95% CI, 0.29 to 1.13; in BRCA2 carriers: HR=0.48; 95% CI, 0.22 to 1.05). Adverse effects (hot flashes, thromboembolism, endometrial cancer) accompany these agents and may limit acceptability to some women.
 
Prophylactic Oophorectomy
In studies limited to BRCA1- and BRCA2-positive women, prophylactic oophorectomy is accompanied by a 50% to 60% reduction in breast cancer risk (Finch, 2014; Kauff, 2002; Rebbeck, 2002). However, the lack of data obtained from a broader set of women with lower penetrance variants limits generalizability (consistent with current NCCN guidelines [V.1.2017]). Accordingly, there is no evidence to support benefit in women outside those with high penetrance variants.
 
Prophylactic Mastectomy
Hartmann and Lindor (2016) reviewed 5 nonrandomized studies (8 publications) of bilateral prophylactic risk reduction mastectomy in women with family histories consistent with hereditary breast cancer, including those with BRCA1 and BRCA2 variants (Domchek, 2010; Evans, 2009; artmann, 1999; Hartmann, 2001; Heemskerk-Gerritsen, 2007; Meijers-Heijboer, 2001; Rebbeck, 2004; Skytte, 2011). Four studies found a 90% or greater reduction in subsequent breast cancer risk while 1 small study (domchek, 2010) found no statistically significant risk reduction (RR=0.39; 95% CI, 0.12 to 1.36). The 2014 USPSTF BRCA screening review concluded: “In high-risk BRCA-related cancer women and women who are variant carriers, risk-reducing mastectomy reduced breast cancer by 85% to 100% and breast cancer mortality by 81% to 100%…. Some women experienced physical complications of surgery, postsurgical symptoms, or changes in body image; some had decreased anxiety.” (neksibm 2013; Neksibm 2014). A 2010 Cochrane reviewed prophylactic mastectomy, but did not pool results (Lostumbo, 2010). Twenty studies of bilateral prophylactic mastectomy (BPM), 12 studies of CPM, and 6 studies examining either procedure were included. Reviewers concluded that bilateral prophylactic mastectomy “should be considered only among those at very high risk of disease.” And that “BPM was effective in reducing both the incidence of, and death from, breast cancer, [though] more rigorous prospective studies (ideally randomized trials) are needed.”
 
Fayanu and colleagues (2014) conducted a systematic review and meta-analysis of studies reporting outcomes following CPM (Fayanu, 2014). Four observational studies were identified including women at increased “familial/genetic risk”—2 studies limited to BRCA carriers (Metcalfe, 2004; van Sprundel, 2005) and 2 studies in women with a family history of breast cancer. There was no apparent impact on overall survival (RR=1.09; 95% CI, 0.97 to 1.24; 3 studies, n=1936) and a lower but not significantly decreased risk of breast cancer mortality (RR=0.66; 95% CI, 0.27 to 1.64; 2 studies, n=918); there were decreased risks of metachronous cancers (RR=0.04; 95% CI, 0.02 to 0.09; I2=0%; 4 studies, n=2418) and distant metastases (RR=0.71; 95% CI, 0.51 to 0.81; 2 studies, n=918).
 
However, 3 recent retrospective studies not included in the meta-analysis suggested improved survival in BRCA carriers following CPM (Heemskerk-Gerritsen, 2007; Evans, 2013; Metcalfe, 2014), Evans and colleagues (2013) compared survival in BRCA-positive women with unilateral breast cancer (n=105) undergoing CPM to women (n=593) having either unilateral mastectomy or local excision and radiotherapy. Diagnoses were made between 1985 and 2010. Women undergoing CPM were followed a median of 8.6 years from CPM and others a median of 8.6 years from surgery. After adjusting for risk-reducing bilateral salpingo-oophorectomy, CPM was associated with improved survival (HR=0.43; 95% CI, 0.20 to 0.95). Metcalfe and colleagues (2014) followed 390 BRCA-positive women with stage I or II breast cancers undergoing a unilateral mastectomy or additional CPM (n=181); overall mean follow-up was 13 years and an average 2.3 years from diagnosis to CPM (Metcalf, 2014). CPM was associated with a decreased risk of breast cancer death (HR=0.52; 95% CI, 0.29 to 0.93) adjusting for potential confounders. A propensity-matched analysis of 79 pairs yielded a lesser and nonsignificant reduction in risk (HR=0.60; 95% CI, 0.34 to 1.06). Heemskerk-Gerritsen and colleagues (2007) studied 583 BRCA-positive women with breast cancer diagnosed between 1980 and 2011 (11.4 years median follow-up from diagnosis) (Heemskerk-Gerritsen, 2007). During follow-up, 342 (42%) chose to have CPM, which was accompanied by improved overall survival (HR=0.49; 95% CI, 0.29 to 0.82). These recent studies suggest that CPM may be accompanied by improved survival in BRCA carriers (Boughey, 2016) implying that those at highest risk of contralateral cancers choosing CPM may benefit.
 
Prophylactic mastectomy can be accompanied by harms. For example, Silva and colleagues (2015) examined outcomes of 20,501 women with unilateral breast cancer from the American College of Surgeons
National Surgery Quality Improvement Program (NSQIP) database (Silva, 2015). A total of 13,268 (64.7%) women underwent unilateral mastectomy and 7233 (35.3%) bilateral procedures. Whether women were at increased risk of hereditary cancers was not reported. Although all had breast reconstruction, autologous reconstructions were more common following unilateral (19.5%) than bilateral mastectomy (8.9%); others underwent implant-based reconstruction. Some complication rates were higher following bilateral mastectomy, regardless of reconstruction type. After implant reconstruction complications occurred in 10.1% after bilateral mastectomy and in 8.8% after unilateral mastectomy. With autologous reconstruction, complications occurred in 21.2% after bilateral mastectomy and in 14.7% after unilateral mastectomy. Transfusion rates were also higher after bilateral mastectomy but with implant reconstruction were low (0.3% after unilateral and 0.8% bilateral mastectomy). Medical complications were relatively infrequent—in about 1% following implant reconstructions and about 3% after autologous reconstructions. The Cochrane review reported complication rates varying from 4% without reconstruction to 49% with reconstruction (Lostumbo, 2010).
 
In women at high risk of hereditary breast cancer, including BRCA1 and BRCA2 carriers, evidence supports a reduction in subsequent breast cancer after BPM or CPM. Decision analyses have also concluded that the impact on breast cancer incidence extends life in high, but not average risk (Portschy, 2014), women. For example, Schrag and colleagues (1997, 2000) modeled the impact of preventive interventions in women with BRCA1 or BRCA2 variants, and examined penetrance magnitudes similar to those estimated for a PALB2 variant. Compared with surveillance, a 30-year-old BRCA carrier with an expected 40% risk of breast cancer and 5% risk of ovarian cancer by age 70 would gain an expected 2.9 years following a prophylactic mastectomy alone and an additional 0.3 years with a prophylactic oophorectomy (Schrag, 1997). A 50-year-old female BRCA carrier with nodenegative breast cancer and a 24% risk of contralateral breast cancer at age 70 would anticipate 0.9 years in improved life expectancy (0.6 years for node-negative disease) following a CPM (Schrag, 2000).
 
Section Summary: Clinical Utility
Evidence concerning preventive interventions in women with PALB2 variants is indirect, relying on studies of high-risk women and BRCA carriers. Compared with other screening modalities, MRI detects more cancers when high-risk women are screened. There is limited evidence that chemoprevention can decrease the risk of invasive cancers in high-risk women; the USPSTF report and NCCN support a chemoprevention option. In high-risk women, prophylactic mastectomy (BPM or CPM) reduces the risk of breast cancer and BPM appears to decrease breast cancer mortality. Decision models project increased life-expectancy, but mastectomy is accompanied by risks of potential harms. Studies have reported that a minority of BRCA carriers choose to undergo BPM (Hartmann, 2016). There is a rationale for the impact of prophylactic mastectomy applying to women with PALB2 variants given penetrance approaching a BRCA variant, albeit with lesser benefit-to-risk calculus. In women at high risk of hereditary breast cancer who would consider preventive interventions, identifying a PALB2 variant provides a more accurate estimated risk of developing breast cancer compared with family history alone and can offer a better understanding of tradeoffs involved.
 
CHEK2 AND BREAST CANCER RISK ASSESSMENT
Clinical Validity
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 (Easton, 2015). Most studies assessing risk of breast cancer associated with CHEK2 are population and family-based case-control studies.
 
A 2015 article by Easton and colleagues reported that the magnitude of relative risk of breast cancer associated with CHEK2-truncating variants is likely to be moderate and unlikely to be high(Easton, 2015). On the basis of 2 large case-control analyses, authors calculated an estimated relative risk of breast cancer associated with CHEK2 variants of 3.0 (90% CI, 2.6 to 3.5) and an absolute risk of 29% by age 80 years.
 
A 2012 meta-analysis by Yang and colleagues examined the risk of breast cancer in whites with the CHEK2 c.1100delC variant (Yang, 2012). A total of 25 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 had a CHEK2 c.1100delC variant and 164 (0.4%) of the controls. The association between CHEK2 c.1100delC variant and breast cancer risk was significant (OR=2.75; 95% CI, 2.25 to 3.36). By subgroup, odds ratios 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.
 
In 2011, Cybulski and colleagues reported on the risk of breast cancer in women with a CHEK2 variant with and without a family history of breast cancer (Cybulski, 2011). A total of 7494 BRCA1-negative breast cancer patients and 4346 controls were genotyped for the 4 CHEK2 founder variants. A truncating variant was present in 227 (3.0%) patients and in 37 (0.8%) controls (OR=3.6; 95% CI, 2.6 to 5.1). The odds ratio was higher for women with a first- or second-degree relative with breast cancer (OR= 5.0; 95% CI, 3.3 to 7.6) than for women with no family history (OR=3.3; 95% CI, 2.3 to 4.7), and if both a first- and second-degree relative were affected with breast cancer, the odds ratio was 7.3 (95% CI, 3.2 to 16.8). Authors estimated the lifetime risk of breast cancer for carriers of CHEK2- truncating variants to be 20% for a woman with no affected relative, 28% for a woman with 1 second-degree relative affected, 34% for a woman with 1 first-degree relative affected, and 44% for a woman with both a first- and second-degree relative affected.
 
In 2008 Weischer and colleagues 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 (Weischer, 2008). 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 odds ratios 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.
 
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 worse prognosis than noncarriers.
 
A 2014 study by Huzarski and colleagues estimated the 10-year survival rate for patients with early-onset breast cancer, with and without CHEK2 variants.63 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 variants 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 hazard ratio comparing carriers of the missense variant to noncarriers was similar, as was the hazard ratio for carriers of a truncating variant and noncarriers.
 
A 2014 study by Kriege and colleagues compared breast cancer outcomes in patients with and without CHEK2 variants (Kriege, 2014). Different study cohorts were combined to compare 193 carriers to 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.
 
In 2012, Weischer and colleagues 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 Breast Cancer Association Consortium conducted in 12 countries (Weischer , 2012). 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 a 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 124 (27%) early deaths, 100 (22%) breast cancer-specific deaths, 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<0.001) and more often had a positive family history of cancer (p<0.001). Multifactorially adjusted hazard ratios for CHEK2 versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; p=0.004) for early death and 1.63 (95% CI, 1.24 to 2.15; p<0.001) for breast cancer-specific death.
 
Section Summary: Clinical Validity
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, and risk estimates, which have been studied in population- and family-based case controls, are subject to bias and overestimation. 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.
 
Clinical Utility
Risk of Developing Breast Cancer in an Individual with a CHEK2 Sequence Variant
Direct evidence of clinical utility for genetic testing in individuals with CHEK2 variants was not identified. As outlined in the section on PALB2, 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, addition of MRI to mammography, and annually), chemoprevention, prophylactic mastectomy, and prophylactic oophorectomy. The evidence for those interventions is outlined the Clinical Utility section for PALB2 and Breast Cancer Risk Assessment.
 
Following the logic applied in the case of PALB2, there is limited evidence that chemoprevention can decrease the risk of invasive cancers in high-risk women; the USPSTF report and NCCN support a chemoprevention option. In high-risk women, prophylactic mastectomy (BPM or CPM) reduces the risk of breast cancer and BPM appears to decrease breast cancer mortality. Decision models project increased life-expectancy, but mastectomy is accompanied by risks of potential harms. Studies have reported that a minority of BRCA carriers choose to undergo BPM (Hartmann, 2016). In contrast to the case of PALB2, where the penetrance approaches that of a BRCA variant, there is unlikely to be a similar benefit-to-risk calculus for women with a CHEK2 variant making a decision about a prophylactic mastectomy. It is unclear that the relative risk associated with CHEK2 variants would increase risk enough beyond that already conferred by familial risk to change screening behavior.
 
Prognosis of Breast Cancer in an Individual with a CHEK2 Sequence Variant
Despite some studies showing potentially poorer outcomes of breast cancer patients who have
CHEK2 variants, it is unclear how such knowledge would be used to alter the treatment of such a patient. 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.
 
ATM AND BREAST CANCER RISK ASSESSMENT
Clinical Validity
In 2016, Marabelli and colleagues reported on a meta-analysis of the penetrance of ATM gene 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 mutations (Marabelli, 2016). The meta-analysis included 19 studies, which were heterogeneous in terms of population, study design, and baseline breast cancer risk. The estimated cumulative 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%).
 
Individual studies have also reported on the association between breast cancer development and pathogenic ATM variants.
 
Clinical Validity
ATM heterozygotes appear to have a relative risk of breast cancer from 2% to 6% of that of the general population, similar to that of CHEK2.
 
Clinical Utility
The chain of evidence supporting the clinical utility for testing for ATM variants in individuals with risk of hereditary breast/ovarian cancer follows that for testing for CHEK2 variants.
 
2018 Update
A literature search conducted using the MEDLINE database through February 2018 did not reveal any new information that would prompt a change in the coverage statement.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2019. No new literature was identified that would prompt a change in the coverage statement.
 
 

CPT/HCPCS:
0102uHereditary breast cancer related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer), genomic sequence analysis panel utilizing a combination of NGS, Sanger, MLPA, and array CGH, with MRNA analytics to resolve variants of unknown significance when indicated (17 genes [sequencing and deletion/duplication])
0129UHereditary breast cancer related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer), genomic sequence analysis and deletion/duplication analysis panel (ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, and TP53)
0131UHereditary breast cancer related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer), targeted mRNA sequence analysis panel (13 genes) (List separately in addition to code for primary procedure)
0136UATM (ataxia telangiectasia mutated) (eg, ataxia telangiectasia) mRNA sequence analysis (List separately in addition to code for primary procedure)
81406Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons) ACADVL (acyl-CoA dehydrogenase, very long chain) (eg, very long chain acyl-coenzyme A dehydrogenase deficiency), full gene sequence ACTN4 (actinin, alpha 4) (eg, focal segmental glomerulosclerosis), full gene sequence AFG3L2 (AFG3 ATPase family gene 3-like 2 [S. cerevisiae]) (eg, spinocerebellar ataxia), full gene sequence AIRE (autoimmune regulator) (eg, autoimmune polyendocrinopathy syndrome type 1), full gene sequence ALDH7A1 (aldehyde dehydrogenase 7 family, member A1) (eg, pyridoxine-dependent epilepsy), full gene sequence ANO5 (anoctamin 5) (eg, limb-girdle muscular dystrophy), full gene sequence ANOS1 (anosmin-1) (eg, Kallmann syndrome 1), full gene sequence APP (amyloid beta [A4] precursor protein) (eg, Alzheimer disease), full gene sequence ASS1 (argininosuccinate synthase 1) (eg, citrullinemia type I), full gene sequence ATL1 (atlastin GTPase 1) (eg, spastic paraplegia), full gene sequence ATP1A2 (ATPase, Na+/K+ transporting, alpha 2 polypeptide) (eg, familial hemiplegic migraine), full gene sequence ATP7B (ATPase, Cu++ transporting, beta polypeptide) (eg, Wilson disease), full gene sequence BBS1 (Bardet-Biedl syndrome 1) (eg, Bardet-Biedl syndrome), full gene sequence BBS2 (Bardet-Biedl syndrome 2) (eg, Bardet-Biedl syndrome), full gene sequence BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (eg, maple syrup urine disease, type 1B), full gene sequence BEST1 (bestrophin 1) (eg, vitelliform macular dystrophy), full gene sequence BMPR2 (bone morphogenetic protein receptor, type II [serine/threonine kinase]) (eg, heritable pulmonary arterial hypertension), full gene sequence BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, Noonan syndrome), full gene sequence BSCL2 (Berardinelli-Seip congenital lipodystrophy 2 [seipin]) (eg, Berardinelli-Seip congenital lipodystrophy), full gene sequence BTK (Bruton agammaglobulinemia tyrosine kinase) (eg, X-linked agammaglobulinemia), full gene sequence CACNB2 (calcium channel, voltage-dependent, beta 2 subunit) (eg, Brugada syndrome), full gene sequence CAPN3 (calpain 3) (eg, limb-girdle muscular dystrophy [LGMD] type 2A, calpainopathy), full gene sequence CBS (cystathionine-beta-synthase) (eg, homocystinuria, cystathionine beta-synthase deficiency), full gene sequence CDH1 (cadherin 1, type 1, E-cadherin [epithelial]) (eg, hereditary diffuse gastric cancer), full gene sequence CDKL5 (cyclin-dependent kinase-like 5) (eg, early infantile epileptic encephalopathy), full gene sequence CLCN1 (chloride channel 1, skeletal muscle) (eg, myotonia congenita), full gene sequence CLCNKB (chloride channel, voltage-sensitive Kb) (eg, Bartter syndrome 3 and 4b), full gene sequence CNTNAP2 (contactin-associated protein-like 2) (eg, Pitt-Hopkins-like syndrome 1), full gene sequence COL6A2 (collagen, type VI, alpha 2) (eg, collagen type VI-related disorders), duplication/deletion analysis CPT1A (carnitine palmitoyltransferase 1A [liver]) (eg, carnitine palmitoyltransferase 1A [CPT1A] deficiency), full gene sequence CRB1 (crumbs homolog 1 [Drosophila]) (eg, Leber congenital amaurosis), full gene sequence CREBBP (CREB binding protein) (eg, Rubinstein-Taybi syndrome), duplication/deletion analysis DBT (dihydrolipoamide branched chain transacylase E2) (eg, maple syrup urine disease, type 2), full gene sequence DLAT (dihydrolipoamide S-acetyltransferase) (eg, pyruvate dehydrogenase E2 deficiency), full gene sequence DLD (dihydrolipoamide dehydrogenase) (eg, maple syrup urine disease, type III), full gene sequence DSC2 (desmocollin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 11), full gene sequence DSG2 (desmoglein 2) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 10), full gene sequence DSP (desmoplakin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 8), full gene sequence EFHC1 (EF-hand domain [C-terminal] containing 1) (eg, juvenile myoclonic epilepsy), full gene sequence EIF2B3 (eukaryotic translation initiation factor 2B, subunit 3 gamma, 58kDa) (eg, leukoencephalopathy with vanishing white matter), full gene sequence EIF2B4 (eukaryotic translation initiation factor 2B, subunit 4 delta, 67kDa) (eg, leukoencephalopathy with vanishing white matter), full gene sequence EIF2B5 (eukaryotic translation initiation factor 2B, subunit 5 epsilon, 82kDa) (eg, childhood ataxia with central nervous system hypomyelination/vanishing white matter), full gene sequence ENG (endoglin) (eg, hereditary hemorrhagic telangiectasia, type 1), full gene sequence EYA1 (eyes absent homolog 1 [Drosophila]) (eg, branchio-oto-renal [BOR] spectrum disorders), full gene sequence F8 (coagulation factor VIII) (eg, hemophilia A), duplication/deletion analysis FAH (fumarylacetoacetate hydrolase [fumarylacetoacetase]) (eg, tyrosinemia, type 1), full gene sequence FASTKD2 (FAST kinase domains 2) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence FIG4 (FIG4 homolog, SAC1 lipid phosphatase domain containing [S. cerevisiae]) (eg, Charcot-Marie-Tooth disease), full gene sequence FTSJ1 (FtsJ RNA methyltransferase homolog 1 [E. coli]) (eg, X-linked mental retardation 9), full gene sequence FUS (fused in sarcoma) (eg, amyotrophic lateral sclerosis), full gene sequence GAA (glucosidase, alpha; acid) (eg, glycogen storage disease type II [Pompe disease]), full gene sequence GALC (galactosylceramidase) (eg, Krabbe disease), full gene sequence GALT (galactose-1-phosphate uridylyltransferase) (eg, galactosemia), full gene sequence GARS (glycyl-tRNA synthetase) (eg, Charcot-Marie-Tooth disease), full gene sequence GCDH (glutaryl-CoA dehydrogenase) (eg, glutaricacidemia type 1), full gene sequence GCK (glucokinase [hexokinase 4]) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence GLUD1 (glutamate dehydrogenase 1) (eg, familial hyperinsulinism), full gene sequence GNE (glucosamine [UDP-N-acetyl]-2-epimerase/N-acetylmannosamine kinase) (eg, inclusion body myopathy 2 [IBM2], Nonaka myopathy), full gene sequence GRN (granulin) (eg, frontotemporal dementia), full gene sequence HADHA (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase [trifunctional protein] alpha subunit) (eg, long chain acyl-coenzyme A dehydrogenase deficiency), full gene sequence HADHB (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase [trifunctional protein], beta subunit) (eg, trifunctional protein deficiency), full gene sequence HEXA (hexosaminidase A, alpha polypeptide) (eg, Tay-Sachs disease), full gene sequence HLCS (HLCS holocarboxylase synthetase) (eg, holocarboxylase synthetase deficiency), full gene sequence HMBS (hydroxymethylbilane synthase) (eg, acute intermittent porphyria), full gene sequence HNF4A (hepatocyte nuclear factor 4, alpha) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence IDUA (iduronidase, alpha-L-) (eg, mucopolysaccharidosis type I), full gene sequence INF2 (inverted formin, FH2 and WH2 domain containing) (eg, focal segmental glomerulosclerosis), full gene sequence IVD (isovaleryl-CoA dehydrogenase) (eg, isovaleric acidemia), full gene sequence JAG1 (jagged 1) (eg, Alagille syndrome), duplication/deletion analysis JUP (junction plakoglobin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 11), full gene sequence KCNH2 (potassium voltage-gated channel, subfamily H [eag-related], member 2) (eg, short QT syndrome, long QT syndrome), full gene sequence KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) (eg, short QT syndrome, long QT syndrome), full gene sequence KCNQ2 (potassium voltage-gated channel, KQT-like subfamily, member 2) (eg, epileptic encephalopathy), full gene sequence LDB3 (LIM domain binding 3) (eg, familial dilated cardiomyopathy, myofibrillar myopathy), full gene sequence LDLR (low den
81408Molecular pathology procedure, Level 9 (eg, analysis of &gt;50 exons in a single gene by DNA sequence analysis)
81479Unlisted molecular pathology procedure

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