Description

BRCA1 and BRCA2 are two distinct tumor suppressor genes involved in a common DNA repair process (Roy et al., 2012). Germline mutations of BRCA genes are associated with an increased risk of breast and ovarian cancer, as well as other cancer types, including pancreatic and prostate cancer to a lesser extent (Paul & Paul, 2014).

“Prior to 2020, the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian (Breast, Ovarian, and Pancreatic as of 2020) focused largely on testing criteria for BRCA1/2 and appropriate risk management for carriers of a BRCA1 or BRCA2 P/LP variant. Sections on LFS and Cowden syndrome/PTEN hamartoma tumor syndrome (PHTS) were also included. Based on strong evidence that genes beyond BRCA1/2, TP53, and PTEN confer markedly increased risk of breast and/or ovarian cancers, these Guidelines have been expanded” (NCCN, 2024b) to include BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53 as high-penetrance breast cancer susceptibility genes, as well as some moderate-penetrance susceptibility genes. These susceptibility genes are often found on multi-gene panels, in addition to BRCA1/2.

Regulatory Status
The Center for Devices and Radiological Health of the Food and Drug Administration (FDA, 2018) granted premarket approval on 1/12/2018 to BRACAnalysis CDx ^® is an in vitro diagnostic device intended for the qualitative detection and classification of variants in the protein coding regions and intron/exon boundaries of the BRCA1 and BRCA2 genes using genomic DNA obtained from whole blood specimens collected in EDTA. Single nucleotide variants and small insertions and deletions (indels) are identified by polymerase chain reaction (PCR) and Sanger sequencing. Large deletions and duplications in BRCA1 and BRCA2 are detected using multiplex PCR. Another FDA-approved device is the “FoundationFocus CDxBRCA,” which is a “is a next generation sequencing based in vitro diagnostic device for qualitative detection of BRCA1 and BRCA2 alterations in formalin-fixed paraffin-embedded (FFPE) ovarian tumor tissue.” This test is intended to be used “as an aid in identifying ovarian cancer patients for whom  treatment with Rubraca (rucaparib) is being considered” (FDA, 2016). A more recent FDA-approved device comes out of Myriad Genetics Inc., the myChoice HRD CDx, which was approved on Oct. 23, 2019. This test is a “next generation sequencing-based in vitro diagnostic test that assesses the qualitative detection and classification of single nucleotide variants, insertions and deletions, and large rearrangement variants in protein coding regions and intron/exon boundaries of the BRCA1 and BRCA2 genes and the determination of Genomic Instability Score (GIS)” based off tumor tissue specimens.

Many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare & Medicaid Services (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). As an LDT, the U.S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.

Policy

Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request. 

The following coverage criteria are designed from National Comprehensive Cancer Network (NCCN) guidelines. “NCCN recommendations have been developed to be inclusive of individuals of all sexual and gender identities to the greatest extent possible. In this [policy], the terms males and females refer to sex assigned at birth.”

Consideration of both maternal and paternal family histories is necessary in the evaluation of an individual’s for risk of carrying a mutation in the BRCA1 or BRCA2 gene; each lineage must be considered separately.   

1. For individuals without a diagnosis of a BRCA-related cancer who are at least 18 years of age, who have received genetic counseling, and who are in a family with a pathogenic familial gene mutation associated with breast cancer, the following testing is considered MEDICALLY NECESSARY:
   1. Testing restricted to the known familial mutation.
   2. Comprehensive genetic testing, including muti-gene panel testing, when the specific familial mutation is unknown.
2. For individuals who have received genetic counseling, multi-gene panel testing (see Note 1, Note 2) for gene mutations associated with breast, ovarian, pancreatic, or prostate cancer is considered MEDICALLY NECESSARY when one of the following conditions are met:
   1. The individual has been diagnosed with breast cancer and meets at least one of the following conditions:
      1. Was diagnosed before 51 years of age.
      2. Was diagnosed at any age with at least one of the following conditions:
         1. High-risk (see Note 3), HER2-negative breast cancer.
         2. Lobular breast cancer with a personal or family history of diffuse gastric cancer.
         3. Metastatic breast cancer.
         4. Triple negative breast cancer.
         5. Two or more primary breast cancer diagnoses.
         6. Male breast cancer.
         7. Has at least one close blood relative (see Note 4) with any of the following:
            1. Breast cancer before 51 years of age.
            2. Breast cancer at any age in a male.
            3. Ovarian cancer at any age.
            4. Pancreatic cancer at any age.
            5. Prostate cancer that is metastatic or a high- or very-high risk group prostate cancer (see Note 5) at any age.
         8. Has a combined total of at least three diagnosed cancers (breast or prostate) in a single lineage of close blood relatives (see Note 4) (including the individual).
      3. Is of Ashkenazi Jewish ancestry
   2. The individual has been diagnosed at any age with ovarian cancer (including fallopian tube cancer or peritoneal cancer).
   3. The individual has been diagnosed at any age with pancreatic cancer.
   4. The individual has been diagnosed at any age with prostate cancer with at least one of the following conditions:
      1. Has metastatic cancer, the tumor has intraductal/cribriform histology, or a high- or very-high risk group (see Note 5).
      2. Has any of the following family history:
         1. Ashkenazi Jewish ancestry.
         2. At least one close blood relative (See Note 4) with any of the following:
            1. Breast cancer before 51 years of age.
            2.  Ovarian cancer at any age.
            3. Pancreatic cancer at any age.
            4. Prostate cancer that is metastatic, tumor with intraductal/cribriform histology, or a high- or very-high risk group (see Note 5) at any age.
         3. Two or more close blood relatives (See Note 4) with either breast or prostate cancer (any grade) at any age.
   5. The individual has a gene mutation associated with breast, ovarian, pancreatic, or prostate cancer that was detected by tumor genomic profiling in the absence of germline mutation testing.
   6. The individual meets testing criteria for Li-Fraumeni syndrome (LFS), Lynch syndrome, or Cowden syndrome/PTEN hamartoma tumor syndrome.
3. For individuals with a known family history of BRCA-related cancer who have received genetic counseling and are at least 18 years of age, multi-gene panel testing (see Note 1, Note 2) for gene mutations associated with breast, ovarian, pancreatic, or prostate cancer is considered MEDICALLY NECESSARY only if the family mutation is unknown (i.e., family member is unavailable for testing or testing results are unavailable) and at least one of the following conditions are met:
   1. The individual has at least one first- or second-degree blood relative (see Note 4) meeting any of the above criteria for an individual with cancer, except as noted below:
      1. Only first-degree relatives of an individual affected with pancreatic cancer should be offered testing.
   2. The individual has a family member with breast, ovarian, tubal, or peritoneal cancer with positive screening results (5-year probability of 5% or greater) from a tool (see Note 6) designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in breast cancer susceptibility genes (BRCA1 or BRCA2).
4. For individuals 18 years of age or older who are of Ashkenazi Jewish ancestry and who do not meet any of the above criteria, testing for the three known founder mutations (185delAG and 5385insC in BRCA1; 6174delT in BRCA2) is considered MEDICALLY NECESSARY.
5. Testing for gene mutations associated with breast, ovarian, pancreatic, or prostate cancer is considered NOT MEDICALLY NECESSARY for any of the following:    
   1. General population screening.
   2. Women diagnosed with breast cancer who are over 65 years of age and who have no close blood relative (see Note 4) with breast, ovarian, pancreatic, or prostate cancer, as there is a low probability that testing will have findings of documented clinical utility.
   3. Individuals diagnosed with localized prostate cancer with Gleason Score <7 and who have no close blood relative (see Note 4) with breast, ovarian, pancreatic, or prostate cancer, as there is a low probability that testing will have findings of documented clinical utility.
   4. In all other situations not specified above.

The following do not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of an individual’s illness.

6. Testing family members for a variant of uncertain significance is considered NOT MEDICALLY NECESSARY.
7. For all other purposes, including, but not limited to, testing of the general population, genetic testing for susceptibility to breast, ovarian, pancreatic, or prostate cancer is considered NOT MEDICALLY NECESSARY.

NOTES:

Note 1: For 2 or more gene tests being run on the same platform, please refer to CAM 235HB-Reimbursement Policy.

Note 2: When germline multigene panel testing is performed in individuals with breast, ovarian, pancreatic, or prostate cancer, the panel should at minimum include the following high-penetrance breast, ovarian, pancreatic, and prostate cancer susceptibility genes: ATM, BRCA1, BRCA2, BRIP1, CDH1, CDKN2A, CHEK2, EPCAM, HOXB13, MLH1, MSH2, MSH6, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53.

Note 3: High-risk disease includes the following:

• The individual has four or more positive lymph nodes.
• The individual has triple negative receptor status cancer.
• The individual has cancer that had an incomplete pathologic response to chemotherapy.

Note 4: Close blood relatives include 1st-degree relatives (e.g., parents, siblings, and children), 2nd-degree relatives (e.g., grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings), and 3rd-degree relatives (great-grandparents, great-aunts, great-uncles, great-grandchildren, and first cousins), all of whom are on the same side of the family.

Note 5: Risk groups are defined in NCCN Guidelines for Prostate Cancer https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

Note 6: According to the USPSTF recommendation in 2019, the risk tools evaluated by the USPSTF include the Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, 7-Question Family History Screening Tool, International Breast Cancer Intervention Study instrument (Tyrer-Cuzick), and brief versions of BRCAPRO. They do not specifically state the preference of one tool over any of the others listed. According to the USPSTF, “these tools should be used to guide referrals to genetic counseling” (USPSTF, 2019).

Table of Terminology

Term	Definition
AA	African American
ACOG	The American College of Obstetricians and Gynecologists
AJ	Ashkenazi Jewish
ASBS	The American Society of Breast Surgeons
ASCO	American Society of Clinical Oncology
ATM	Ataxia telangiectasia mutated
BRCA	Breast cancer gene
BRCA1	Breast cancer gene 1
BRCA2	Breast cancer gene 2
CDH1	cadherin 1
CDRH	Center for Devices and Radiological Health
CHEK2	Checkpoint kinase 2
CLIA ’88	Clinical Laboratory Improvement Amendments of 1988
CMS	Centers for Medicare & Medicaid Services
CRPC	Castrate-resistant prostate cancer
dMMR	Mismatch despair deficiency
DNA	Deoxyribonucleic acid
EDTA	Ethylenediamine tetraacetic acid
ER	Estrogen receptor
FANCC	FA complementation group c
FDA	Food and Drug Administration
FFPE	Formalin-fixed paraffin-embedded
FGFR2	Fibroblast growth factor receptor 2
GIS	Genomic instability score
HBOC	Hereditary Breast and Ovarian Cancer
HER-2	Human epidermal growth factor 2
LDTs	Laboratory-developed tests
LFS	Li-Fraumeni syndrome
MSH2	Muts homolog 2
MSI	Microsatellite instability
NBN	Nibrin
NCCN	National Comprehensive Cancer Network
NGS	Next-generation sequencing
NICE	National Institute for Health and Care Excellence
OCCR	Ovarian cancer cluster region
PALB2	Partner and localizer of brca2
PARP	Poly ADP-ribose polymerase
PCR	Polymerase chain reaction
PMS2	Pms1 homolog 2, mismatch repair system component
PR	Progesterone receptor
PTEN	Phosphatase and tensin homolog
RAD51C	Rad51 paralog c
RAD51D	RAD51 homolog C
RECQL	RecQ Like Helicase
RET	Ret proto-oncogene
SMARCA4	Swi/snf related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4
TMB	Tumor mutational burden
TP53	Tumor protein p53
USPSTF	The U.S. Preventive Services Task Force

Rationale

 

BRCA1 and BRCA2 are critical genes in the process of homologous recombination repair of double-strand DNA breaks (Walsh, 2015). Both genes are very large (occupying about 70 kb) and encode a combined total of 49 exons. They are considered tumor suppressor genes and a loss of function on either gene increases the cancer risk (Pan & Xie, 2017). BRCA1 is thought to regulate c-Abl kinase activity (as loss of BRCA1 results in a constitutively activated c-Abl kinase) whereas BRCA2 is thought to regulate Rad51, which repairs DNA damage such as chromosomal breaks (Yoshida & Miki, 2004). 

Different regions of mutation may confer different types of risk. For example, BRCA2 has an area called the ovarian cancer cluster region (OCCR) in which mutations predispose the patient for ovarian cancer. Mutations outside the OCCR are more likely to result in breast cancer compared to mutations in the OCCR. On BRCA1, mutations closer to the 3’ end of the gene may result in higher risk than mutations closer to the 5’ end (Meric-Bernstam et al., 2013). Other gene defects that affect homologous recombination include hypermethylation of RAD51C or ATR mutation. However, these are considered to have a phenotype of “BRCAness” and behave like BRCA-deficient genes even if the BRCA gene itself is normal (Walsh, 2015).

Although the probability of cancer development in carriers is variable, estimates of penetrance in individuals with a pathogenic variant in BRCA1 or BRCA2 range from 46% to 87% lifetime risk for breast cancer, and 16.5% to 63% lifetime risk for ovarian cancer (Petrucelli et al., 2016). BRCA1 and BRCA2 mutations account for about 5% – 10% of breast cancers and 10% – 18% of ovarian cancers (Walsh, 2015). BRCA mutations are inherited in an autosomal dominant fashion and are highly penetrant (Isaacs & Peshkin, 2024).

It is clinically important to recognize these carriers to guide management of cancer and identify unaffected women with a BRCA mutation who will benefit from enhanced surveillance; in addition, recognizing carriers helps physicians tailor care to improve outcomes and more efficiently use health-care resources. Adherence to guidelines for managing cancer risk has the potential to have a significant individual and population health impact on morbidity and mortality (Buchanan et al., 2017). For example, BRCA deficient cancers are often targeted for a certain class of drugs called poly(ADP-ribose) polymerase (PARP) inhibitors. These inhibitors target enzymes responsible for the base excision repair pathway. A cell can survive with the loss of either the base excision repair pathway or the homologous recombination mechanism, but not both. Since BRCA-deficient cells already have a faulty homologous recombination mechanism, the BRCA-deficient cell dies when the PARP inhibitor shuts down the base excision repair pathway. BRCA-deficient cells have been shown to be affected 1000 times more by these PARP inhibitors than wild-type cells (Walsh, 2015).

Numerous proprietary tests exist for the assessment of BRCA or its related genes such as RAD51. For example, gene panels such as Ambry Genetics’ panel include 25 genes such as BRCA1, BRCA2, CHEK2, ATM, RAD51C, and BRIP1. This test is performed by next generation sequencing or Sanger sequencing (except for EPCAM) with a turnaround time of 2 – 3 weeks. Ambry has several proprietary tests such BRCAplus and BreastNext (Ambry, 2023). Another gene panel that has been developed to identify genetic mutations associated with inherited breast and ovarian cancers is the AmpliSeq for Illumina BRCA Plus, Extended Hereditary Breast and Ovarian Research Panel. This panel assesses germline variants in 11 genes known to harbor mutations related to breast and ovarian cancer: ATM, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, NBN, CDH1, SMARCA4, and TP53. However, though these community panels boasts the convenience of being made-to-order, Illumina warns that they do not have associated performance metrics (Illumina, 2021). myChoice CDx by Myriad Genetics, Inc. is a tumor test that determines homologous recombination deficiency status by detecting BRCA1 and BRCA2 (sequencing and large rearrangement) variants. This next generation sequencing-based in vitro diagnostic assay focuses on assessing genomic instability by using loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions from tumor tissue specimens. The results can then be used to guide treatment and therapy for ovarian cancer patients with positive homologous recombination deficiency, which is defined by the presence of BRCA1/2 mutations and/or positive Genomic Instability Score (Myriad Genetics, 2024).

Clinical Utility and Validity
A study performed by Kuchenbaecker et al. (2017) assessed the cumulative risk of breast and ovarian cancer based on mutation position. A sample of 9,856 patients was analyzed, with 6036 patients carrying a BRCA1 mutation and 3820 with a BRCA2 mutation. 5046 patients were unaffected by either type of cancer and 4,810 had breast cancer, ovarian cancer, or both at baseline. The breast cancer assessment was based on 3886 carriers, and the ovarian cancer assessment was based on 5,066 women. The authors evaluated the cumulative risk of breast cancer to 80 years to be 72% for BRCA1 mutation carriers and 69% for BRCA2 carriers. Cumulative risk for ovarian cancer to 80 years was found to be 44% for BRCA1 carriers and 17% for BRCA2 carriers. BRCA2 mutations outside the OCCR were found to have a higher risk of breast cancer than mutations inside it (hazard ratio: 1.93 for OCCR ranges 5′ to c.2830, c.2831 to c.6401, c.6402 to 3) but no difference in overall ovarian cancer risk. Mutations closer to the 3’ or 5’ ends of BRCA1 were found to have a higher risk of breast cancer compared to the middle third of the gene and the third closest to the 3’ end had the highest hazard ratio of 1.51 compared to the third closest to the 5’ end (1.43) (Kuchenbaecker et al., 2017).

A meta-analysis of 44 articles was performed to assess the difference in risk factors between BRCA1 and BRCA2 carriers. Factors such as breastfeeding, coffee, infertility, and more were examined between both genotypes, and the only risk factor that revealed an association of any kind was age at first live birth for BRCA1 carriers. Breast cancer risk was found to decrease for BRCA1 women over 30 compared to women under 30, and the same was found for women from 25-29 compared to women under 25. However, the authors stressed that more research was required (Friebel et al., 2014).

However, the importance of BRCA testing has not only been explored for lifestyle choices or transient states; factors such as ethnicity can also play a role in the predisposition of patients to breast cancer. Palmer et al. (2020) delved into the risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes. Using germline DNA samples and drawing from 10 epidemiologic studies encompassing 5054 affected African American women and 4993 unaffected African American women, Palmer et al. (2020) sequenced mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel and found that pathogenic mutations could be identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with an overall increased risk for breast cancer, while RAD51D mutations were observed specifically to be linked to higher risk of ER-negative disease. Other mutations the researchers found to be of interest were in CHEK2, ATM, ERCC3, FANCC, and RECQL. Thus, it was concluded that the study corroborated the use and “validity of current breast cancer testing panels for use in AA women” (Palmer et al., 2020).

A study using next generation sequencing (NGS) to identify BRCA mutations was performed by Lang et al. 4,034 patients were screened (2991 breast cancer patients, 1,043 healthy controls). BRCA mutations were found in 247 of the breast cancer patients or 8.3%. 13.9% (16/115) of the BRCA1 mutations were of the “c.5470_5477del” variation, and several clinical characteristics such as high KI67 index and high tumor grade were related to BRCA mutations, BRCA2 carriers were also found to have poorer disease-free survival among HER2 positive patients (Lang et al., 2017).

Tomao et al. (2019) investigated the ability of BRCA mutational status on predicting hematologic toxicity with platinum-based chemotherapy. 176 patients were included, with 58 BRCA mutation carriers (40 BRCA1, 18 BRCA2, 118 controls). The authors identified several differences in hematologic toxicity between the two groups; the BRCA positive group was observed to have significantly higher frequency in “thrombocytopenia (24% vs 5%), anemia (21% vs 7%; p = 0.006) and neutropenia (62% vs 27%)”. The authors also noted that granulocyte-colony stimulating growth factors injection (12% versus 1%,) and dose delay (19% versus 27%) were more likely in the BRCA positive group (odds ratio = 2.567 for granulocyte-colony stimulating growth factors injection and 3.860 for dose delay). Overall, the authors concluded that “germline BRCA ½ mutations are associated with a higher hematologic toxicity in patients with ovarian cancer who underwent platinum-based chemotherapy” (Tomao et al., 2019).

Yoo et al. (2020) conducted BRCA1/NGS for 262 hereditary breast and ovarian cancer (HBOC) syndrome patients, and the results were confirmed by using multiplex ligation-dependent probe amplification and direct Sanger sequencing. A multigene panel test was also performed on 120 patients who did not possess BRCA1/2 pathogenic variants but who met NCCN criteria for testing. The researchers reported that pathogenic variants in BRCA1/2 were detected in 30 HBOC patients (11.5%), and four out of the 120 patients possessed pathogenic variants of MSH2 PMS2, CHEK2 and PALB2, which were also detectable by multigene panel testing. The results suggested to the authors that “Multi-gene panel testing could be a significant screening tool for HBOC patients, especially for those with a family history of cancer” (Yoo et al., 2020).

BRCA testing has been demonstrated to be potentially beneficial, even when the testing is unselected and is population-based. Manchanda et al. (2020) examined the North London Ashkenazi-Jewish (AJ) population in a randomized controlled trial consisting of 1034 AJ women and men across two arms — one, a population-screening approach, and a second, a family history/clinical-criteria-based BRCA testing—to determine subsequent effects on psychological health and quality of life after providing genetic testing for three Jewish BRCA founder-mutations. Based on the results of the study, the researchers drew the conclusion that “Population-based AJ BRCA testing does not adversely affect long-term psychological wellbeing or quality-of-life, decreases anxiety and could identify up to 150% additional BRCA carriers” (Manchanda et al., 2020). However, these results on the anxiety and health-anxiety of this population may be contested, for validated questionnaires were used to measure the psychological wellbeing of the participants at baseline/1-year/2-year/3-year follow-ups. Moreover, the participants were recruited through self-referral, which may affect the internal validity of the trials.

National Comprehensive Cancer Network (NCCN)
NCCN guidelines titled Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Version 3.2024 address general hereditary cancer testing. Note that NCCN recommendations have been developed to be inclusive of individuals of all sexual and gender identities to the greatest extent possible. In this guideline, the terms males and females refer to sex assigned at birth. The NCCN list the following scenarios as “clinically indicated” for genetic testing:

1. “Individual with any blood relative with a known pathogenic/likely pathogen variant in a cancer susceptibility gene” [including BRCA1/2]
2. “Individuals meeting the criteria below but tested negative with previous limited testing, (e.g., single gene and/or absent deletion duplication analysis) and are interested in pursuing multi-gene testing”
3. “A pathogenic/likely pathogenic variant identified on tumor genomic testing that has clinical implications if also identified in the germline”
4. “To aid in systemic therapy and surgical decision-making”
5. “Individual who meets Li-Fraumeni syndrome (LFS) testing criteria or Cowden syndrome/PTEN hamartoma tumor syndrome testing criteria or Lynch syndrome”
6. Personal or family history of cancer
   1. Testing for high-penetrance breast cancer susceptibility genes (Specifically BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11 and TP53)aa. Personal history of breast cancer with specific features:
      1. By Age of diagnosis and family history
         • Diagnosed at age ≤50y
         • Diagnosed at any age:

• Treatment indications:
  • To aid in systematic treatment decisions using PARP inhibitors for breast cancer in the metastatic setting
  • To aid in adjuvant treatment decisions with Olaparib for high-risk, HER-2 negative breast cancer

• Pathology/histology:
  • Triple-negative breast cancer
  • Multiple primary breast cancers (synchronous or metasynchronous)
  • Lobular breast cancer with personal or family history of diffuse gastric cancer
• Family history:
  • ≥ 1 close blood relative with ANY:
  • Breast cancer at age ≤ 50y
  • Male breast cancer
  • Ovarian cancer
  • Pancreatic cancer
  • Prostate cancer with metastatic or high- or very-high-risk group
    •  ≥ 3 total diagnoses of breast and/or prostate cancer (any grade) on the same side of the family including the patient with breast cancer.
• Ancestry:
  • Ashkenazi Jewish Ancestry
• Male breast cancer
  • Family history of cancer only
    •  Individuals affected with breast cancer (not meeting testing criteria listed above) or individual unaffected with breast cancer with a first- or second-degree blood relative meeting any of the criteria listed above (except unaffected individuals whose relatives meet criteria only for systemic therapy decision-making).
    • Individuals affected or unaffected with breast cancer who otherwise do not meet the criteria above but have a probability > 5% of a BRCA1/2 P/LP variant based on prior probability models (eg, Tyrer-Cuzick, BRCAPro, CanRisk)

1. Testing for ovarian cancer susceptibility genes
   1. Personal history of epithelial ovarian cancer (including fallopian tube cancer or peritoneal cancer) at any age
   2. Family history of cancer only
      1. An individual unaffected with ovarian cancer with a first- or second-degree blood relative with epithelial ovarian cancer (including fallopian tube cancer or peritoneal cancer) at any age
      2. An individual unaffected with ovarian cancer who otherwise does not meet the criteria above but has a probability > 5% of a BRCA1/2 pathogenic variant based on prior probability models (e.g., Tyrer-Cuzick, BRCAPro, CanRisk)
2. Testing for pancreatic cancer susceptibility genes
   1. Exocrine pancreatic cancer
      1. All individuals diagnosed with exocrine pancreatic cancer
      2. First-degree relatives of individuals diagnosed with exocrine pancreatic cancer
3. Testing for high-penetrance prostate cancer susceptibility genes
   1. Personal history of prostate cancer with specific features:
      1. By tumor characteristics (any age)
         1. Metastatic
         2. Histology
            1. High- or very-high-risk group
      2. By family history and ancestry
         1. ≥ 1 close blood relative with:
            1. breast cancer at age ≤ 50 y
            2. triple-negative breast cancer at any age
            3. male breast cancer at any age
            4. ovarian cancer any age
            5. pancreatic cancer any age
            6. metastatic, or high- or very-high risk group at any age
         2. ≥ 3 close blood relatives with prostate cancer (any grade) and/or breast cancer on the same side of the family including the patient with prostate cancer
         3. Ashkenazi Jewish ancestry
      3. Family history of cancer only
         1. An affected (not meeting testing criteria listed above) or unaffected individual with a first-degree blood relative meeting any of the criteria listed above (except unaffected individuals whose relatives meet criteria only for systemic therapy decision-making)
4. Testing for Li-Fraumeni Syndrome
   1. Individual from a family with a known TP53 pathogenic/likely pathogenic variant
   2. Classic Li-Fraumeni syndrome (LFS) criteria:
      1. Combination of an individual diagnosed at age < 45 years with a sarcoma AND
      2. A first-degree relative diagnosed at age < 45 years with cancer AND
      3. An additional first- or second-degree relative in the same lineage with cancer diagnosed at age < 45 years, or a sarcoma at any age
   3. Chompret criteria:
      1. Individual with a tumor from LFS tumor spectrum (e.g., soft tissue sarcoma, osteosarcoma, CNS tumor, breast cancer, adrenocortical carcinoma), before 46 years of age, AND at least one first- or second-degree relative with any of the aforementioned cancers (other than breast cancer if the proband has breast cancer) before the age of 56 years or with multiple primaries at any age OR
      2. Individual with multiple tumors (except multiple breast tumors), two of which belong to LFS tumor spectrum with the initial cancer occurring before the age of 46 years OR
      3. Individual with adrenocortical carcinoma, or choroid plexus carcinoma or rhabdomyosarcoma of embryonal anaplastic subtype, at any age of onset, regardless of family history OR
      4. Breast cancer before 31 years of age
   4. Personal or family history of pediatric hypodiploid acute lymphoblastic leukemia
   5. In individuals with cancer with a pathogenic/likely pathogenic TP53 variant identified on tumor-only genomic testing, germline testing should be considered for: (1) Those meeting one or more of the other LFS testing criterion above after reevaluation of personal and family history (2) those diagnosed age < 30 years with any cancer (3) those with clinical scenario not meeting these criteria but warranting germline evaluation per clinician discretion.
5. Testing for Cowden Syndrome (CS)/PTEN Hamartoma Tumor Syndrome (PHTS):
   1. Individual from a family with a known PTEN pathogenic/likely pathogenic variant
   2. Individual with a personal history of Bannayan-Riley-Ruvalcaba syndrome (BRRS)
   3. Individual meeting clinical diagnostic criteria for CS/PHTS
   4. Individual not meeting clinical diagnostic criteria for CS/PHTS with a personal history of:
      1. Adult Lhermitte-Duclos disease (cerebellar tumors); or
      2. Autism spectrum disorder and macrocephaly; or
      3. Two or more biopsy-proven trichilemmomas; or
      4. Two or more major criteria (one must be macrocephaly); or
      5. Three major criteria, without macrocephaly; or
      6. One major and ≥3 minor criteria; or
      7. ≥ 4 minor criteria
      8. Individual with a relative with a clinical diagnosis of CS/PHTS or BRRS for whom testing has not been performed
         1. The individual must have the following:
            1. Any one major criterion or
               1. Breast cancer
               2. Endometrial cancer
               3. Follicular thyroid cancer
               4. Multiple GI hamartomas or ganglioneuromas
               5. Macrocephaly (megalocephaly) (i.e., ≥ 97%, 58 cm in adult female, 60 cm in adult male)
               6. Macular pigmentation of glans penis
               7. Mucocutaneous lesions
                  1. One biopsy-proven trichilemmoma
                  2. Multiple palmoplantar keratoses
                  3. Multifocal or extensive oral mucosal papillomatosis
                  4. Multiple cutaneous facial papules (often verrucous)
            2. Two minor criteria
               1. Autism spectrum disorder
               2. Colon cancer
               3. ≥ 3 esophageal glycogenic acanthoses
               4. Lipomas
               5. Intellectual disability (i.e., IQ ≤ 75)
               6. Papillary or follicular variant of papillary thyroid cancer
               7. Thyroid structural lesions (e.g., adenoma, nodule[s], goiter)
               8. Renal cell carcinoma
               9. Single GI hamartoma or ganglioneuroma
               10. Testicular lipomatosis
               11. Vascular anomalies (including multiple intracranial developmental venous anomalies)
      9. PTEN pathogenic/likely pathogenic variant detected by tumor genomic testing on any tumor type in the absence of germline analysis

The NCCN states that general hereditary cancer testing may be considered in the following scenario (with appropriate pre-test education and access to post-test management):

• An individual of Ashkenazi Jewish ancestry without additional risk factors.
• Personal history of serious endometrial cancer.

The NCCN states that testing for high-penetrance breast cancer susceptibility genes may be considered in the following scenarios (with appropriate pre-test education and access to post-test management):

1. Personal history of breast cancer < 60 y not meeting any of the above criteria may approach a 2.5% probability of having a pathogenic/likely pathogenic variant, based on recent data. It is cautioned that many of those PVs will be in moderate penetrance genes, which are over-represented in older affected individuals. Access to an experienced genetic counseling team to discuss management options is particularly important in this setting.
2. Personal history of breast cancer diagnosed at any age with ≥1 close blood relative with intermediate-risk prostate cancer with intraductal/cribriform histology.
3. Individuals affected or unaffected with breast cancer who otherwise do not meet any of the above criteria but with a 2.5%-5% probability of BRCA 1/2 pathogenic variant/likely pathogenic variant based on prior probability models (e.g. Tyrer-Cuzick, BRCAPro, CanRisk).

The NCCN states that when testing for high-penetrance breast cancer susceptibility genes, there is “a low probability (< 2.5%) that testing will have findings of documented high-penetrance genes in the following scenarios:

1. Female diagnosed with breast cancer at age > 60 y, with no close relative with breast, ovarian, pancreatic, or prostate cancer
2. Diagnosed with localized prostate cancer with Gleason Score <7 and no close relative with breast, ovarian, pancreatic, or prostate cancer" (NCCN, 2024b).

The NCCN suggests that prior to genetic testing, 

• “The probability of pathogenic or likely pathogenic variant detection associated with these criteria will vary based on family structure, which includes size of the family, age of the family members, early death, adoption, and number of male and female relatives. Individuals with unknown or limited family history/structure, such as fewer than 2 female first- or second-degree relatives having lived beyond age 45 in either lineage, may have an underestimated probability of familial P/LP variant detection. The estimated likelihood of P/LP variant detection may be low in families with many unaffected and/or male relatives.
• Patients who have received an allogeneic bone marrow transplant or with active or recent hematologic malignancies should not have molecular genetic testing via blood, saliva, or buccal samples (due to unreliable test results from contamination by donor DNA) until other technologies are available. If available, DNA should be extracted from a fibroblast culture. If this source of DNA is not possible, buccal samples can be considered, subject to the risk of donor DNA contamination or malignant cells from the hematologic malignancy.
• If more than one family member is affected with cancers highly associated with a particular inherited cancer susceptibility syndrome, consider initial testing of a family member with youngest age at diagnosis, bilateral disease, multiple primary cancers, or other cancers associated with the syndrome, or most closely related to the proband/patient. If there are no available family members with cancer that is a cardinal feature of the syndrome in question, consider testing first- or second-degree family members affected with other cancers thought to be related to the gene in question (eg, prostate or pancreas with BRCA1/2).
• Testing for unaffected family members when no affected member is available should be considered. Significant limitations of interpreting test results should be discussed.
• In children < 18 y, genetic testing is generally not recommended when results would not impact medical management.
• Likely pathogenic variants are usually clinically managed similarly to pathogenic variants, while patients with variants of uncertain significance (VUS) and likely benign variants should be managed based on the cancers present in the family.
• Choice of multi-gene testing” (NCCN, 2024b).

Furthermore, in the situation where the presence of a pathogenic or likely pathogenic variant is unknown, the NCCN recommends that “the testing of the unaffected individual (or of unaffected family members) should only be considered when no affected family member is available for testing. In such cases, the unaffected individual or unaffected close relative with the highest likelihood of testing positive for the pathogenic or likely pathogenic variant should be tested,” though “A negative test result in such cases, however, is considered indeterminate and does not provide the same level of information as when there is known pathogenic or likely pathogenic variant in the family.” The NCCN also remarks that “testing multiple family members may be indicated” when testing unaffected individuals “(in the absence of having tested affected family members)” to aid in interpreting results (NCCN, 2024b).

The NCCN also recommends assessing BRCA1/2 in all patients with recurrent or metastatic breast cancer to identify candidates for PARP inhibitor therapy (NCCN, 2024a).

Regarding BRCA in ovarian cancer, the NCCN recommends testing for BRCA1/2 mutations prior to initiating treatment for persistent/recurrent ovarian cancer since “germline and/or somatic BRCA1/2 status informs maintenance therapy.” The NCCN notes that BRCA testing may be done prior to this stage (NCCN, 2024c).

BRCA testing was also mentioned in guidelines for pancreatic adenocarcinoma. The NCCN recommends tumor/somatic gene profiling for those with “locally advanced/metastatic disease who are candidates for anti-cancer therapy to identify uncommon mutations, including testing for mutations in BRAF, BRCA1/2, HER2, KRAS, and PALB2 genes, fusions in ALK, NRG1, NTRK, ROS1, FGFR2, RET genes, microsatellite instability (MSI), mismatch repair deficiency (dMMR) , or tumor mutational burden (TMB) via an FDA-approved and/or validated next-generation sequencing (NGS)- based assay” (NCCN, 2024d).

The NCCN also published guidelines regarding BRCA in prostate cancer. Germline genetic testing, which should include BRCA1/2 among other genes, such as ATM, PALB2, and CHEK2 was recommended for initial patients with prostate cancer and any of the following: “a positive family history; high-risk, very-high-risk, regional, or metastatic prostate cancer, regardless of family history; Ashkenazi Jewish ancestry; [and] a personal history of breast cancer.” The NCCN also notes that “germline genetic testing should be considered in patients with a personal history of prostate cancer and 1) intermediate-risk prostate cancer and intraductal/cribriform histology or 2) a personal history of exocrine pancreatic cancer, breast cancer, colorectal, gastric, melanoma, pancreatic cancer, upper tract urothelial cancer, glioblastoma, biliary tract cancer, and small intestinal cancer” Moreover, the NCCN asserts that germline testing should include “MLH1, MSH2, MSH6, and PMS2 (for Lynch syndrome) and homologous recombination genes BRCA1, BRCA2, ATM, PALB2, and CHEK2”, urging that cancer predisposition next-generation sequencing be considered (NCCN, 2024e).

Regarding somatic tumor testing in risk groups: 

• “Tumor testing for somatic homologous recombination gene mutations (eg, BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2, CDK12) can be considered in patients with regional (N1) prostate cancer and is recommended for those with metastatic disease.
• Tumor testing for MSI or dMMR can be considered in patients with regional or metastatic castration-naïve prostate cancer and is recommended in the metastatic castrate-resistant prostate cancer (CRPC) setting.
• Tumor mutational burden (TMB) testing may be considered in patients with metastatic CRPC.
• Multigene molecular testing can be considered for patients with low-, intermediate-, and high-risk prostate cancer and life expectancy ≥10 years.
• The Decipher molecular assay is recommended to inform adjuvant treatment if adverse features are found post-radical prostatectomy and can be considered as part of counseling for risk stratification in patients with PSA resistance/recurrence after radical prostatectomy (category 2B)” (NCCN, 2024e).

The NCCN published information on TP53 as a pathogenic/likely pathogenic variant, noting that testing for Li-Fraumeni syndrome should occur when the individual is from a family with a known TP53 pathogenic/likely pathogenic variant. They specifically note that when this gene is “included as part of a multi-gene panel, an individual does not need to meet these testing criteria [for Li-Fraumeni syndrome]- if “testing criteria on other testing criteria pages are met” (NCCN, 2024b).

The U.S. Preventive Services Task Force (USPSTF) 
In 2019, the USPSTF updated their 2014 recommendation (Moyer, 2014). In it, they state that “the USPSTF recommends that primary care clinicians assess women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with breast cancer susceptibility 1 and 2 (BRCA1/2) gene mutations with an appropriate brief familial risk assessment tool. Women with a positive result on the risk assessment tool should receive genetic counseling and, if indicated after counseling, genetic testing.” This recommendation is intended for women with a “personal or family history of breast, ovarian, tubal, or peritoneal cancer or an ancestry associated with BRCA1/2 gene mutation” (USPSTF, 2019).

Moreover, they do not recommend (i.e., issue a D recommendation) routine screening, genetic testing, or genetic counseling for women who have no family or personal history of breast cancer or whose ancestry or ethnicity is not associated with a higher risk for potentially pathogenic BRCA1 or BRCA2 gene mutations (USPSTF, 2019).

The American College of Obstetricians and Gynecologists (ACOG)
The ACOG released guidelines in 2019 for Hereditary Cancer Syndromes and Risk Assessments. The ACOG recommends: 

• Evaluating a patient’s risk of hereditary breast and ovarian cancer syndrome should be a routine part of obstetric and gynecologic practice. Initial risk evaluation should include a personal medical history and family history.
• Genetic testing is recommended when the results of a detailed risk assessment that is performed as part of genetic counseling suggest the presence of an inherited cancer syndrome for which specific genes have been identified and when the results of testing are likely to influence medical management.
• The two main genetic testing options for hereditary breast and ovarian cancer syndrome are BRCA mutation testing and multigene panel testing that includes both BRCA and other genetic mutations. Multigene panel testing may be useful when more than one gene may be associated with an inherited cancer syndrome or when a patient has a personal or family history that is consistent with an inherited cancer susceptibility, but single-gene testing has not identified a pathogenic variant (ACOG, 2019).

The American Society of Breast Surgeons (ASBS) 
The American Society of Breast Surgeons have released guidelines on genetic testing for hereditary breast cancer. They are as follows: 

1. “Breast surgeons, genetic counselors, and other medical professionals knowledgeable in genetic testing can provide patient education and counseling and make recommendations to their patients regarding genetic testing and arrange testing”
2. “Genetic testing should be made available to all patients with a personal history of breast cancer. Recent data support that genetic testing should be offered to each patient with breast cancer (newly diagnosed or with a personal history). If genetic testing is performed, such testing should include BRCA1/BRCA2 and PALB2, with other genes as appropriate for the clinical scenario and family history. For patients with newly diagnosed breast cancer, identification of a mutation may impact local treatment”
3. “Patients who had genetic testing previously may benefit from updated testing. Every patient being seen by a breast surgeon, who had genetic testing in the past and no pathogenic variant was identified, should be re-evaluated and updated testing considered. In particular, a patient who had negative germline BRCA1 and 2 testing, who is from a family with no pathogenic variants, should be considered for additional testing.1 Genetic testing performed prior to 2014 most likely would not have had PALB2 or other potentially relevant genes included and may not have included testing for large genomic rearrangements in BRCA1 or BRCA2”
4. “Genetic testing should be made available to patients without a history of breast cancer who meet NCCN guidelines. Unaffected patients should be informed that testing an affected relative first, whenever possible, is more informative than undergoing testing themselves. When it is not feasible to test the affected relative first, then the unaffected family member should be considered for testing if they are interested, with careful pre-test counseling to explain the limited value of “uninformative negative” results. It is also reasonable to order a multi-gene panel if the family history is incomplete (i.e., a case of adoption, patient is uncertain of exact type of cancer affecting family members, among others) or other cancers are found in the family history, as described above” (Manahan et al., 2019).

American Society of Clinical Oncology (ASCO) 
ASCO recommends germline genetic testing for BRCA1/2 for all women diagnosed with epithelial ovarian cancer. Somatic tumor testing for BRCA1/2 should be performed in women that do not carry a germline pathogenic or likely pathogenic variant (Konstantinopoulos et al., 2020).

ASCO also published a guideline regarding PARP inhibitors for ovarian cancer. In recommendation 2.2, they recommend the use of “Myriad myChoice CDx” to determine BRCA1/2 status for therapy decisions (Tew et al., 2020).

In 2024, ASCO published “Germline Testing in Patients With Breast Cancer: ASCO-Society of Surgical Oncology Guideline” with the following recommendations:

• “BRCA1/2 mutation testing should be offered to all newly diagnosed patients with breast cancer ≤65 years and select patients >65 years based on personal history, family history, ancestry, or eligibility for poly(ADP-ribose) polymerase (PARP) inhibitor therapy.”
• “All patients with recurrent breast cancer who are candidates for PARP inhibitor therapy should be offered BRCA1/2 testing, regardless of family history. BRCA1/2 testing should be offered to women who develop a second primary cancer in the ipsilateral or contralateral breast.”
• “For patients with prior history of breast cancer and without active disease, testing should be offered to patients diagnosed ≤65 years and selectively in patients diagnosed after 65 years, if it will inform personal and family risk.”
• “Testing for high-penetrance cancer susceptibility genes beyond BRCA1/2 should be offered to those with supportive family histories; testing for moderate-penetrance genes may be offered if necessary to inform personal and family cancer risk.”
• “Patients should be provided enough pretest information for informed consent; those with pathogenic variants should receive individualized post-test counseling. Variants of uncertain significance should not impact management, and patients with such variants should be followed for reclassification.”
• “Referral to providers experienced in clinical cancer genetics may help facilitate patient selection and interpretation of expanded testing, and provide counseling of individuals without pathogenic germline variants but with significant family history” (Bedrosian et al., 2024).

National Institute for Health and Care Excellence (NICE)
NICE updated their guidelines on familial breast cancer in 2019. In it, they maintain their BRCA-related recommendations from 2013, which are as follows:

“Offer genetic testing in specialist genetic clinics to a relative with a personal history of breast and/or ovarian cancer if that relative has a combined BRCA1 and BRCA2 mutation carrier probability of 10% or more.”

“Offer genetic testing in specialist genetic clinics to a person with no personal history of breast or ovarian cancer if their combined BRCA1 and BRCA2 mutation carrier probability is 10% or more and an affected relative is unavailable for testing.”

“Offer genetic testing in specialist genetic clinics to a person with breast or ovarian cancer if their combined BRCA1 and BRCA2 mutation carrier probability is 10% or more” (NICE, 2019).

European Expert Group
A group of 19 experts in BRCA testing were convened to publish this set of guidelines. These experts came from across Europe and Israel, and participants included clinical or medical geneticists (32%), oncologists (37%), and gynaecologists (26%). 

The guidelines state that with the rise of next-generation sequencing, hotspot testing instead of complete sequencing is “not acceptable,” albeit noting a possible exception of founder mutations representing >99% of pathogenic variants in a specific area.

A majority of experts (60%) voted that BRCA testing should be offered to all patients with metastatic breast cancer (Singer et al., 2019).

In 2021, the group published guidance on BRCA and HRR deficiency testing for recently diagnosed patients with ovarian cancer. Consensus statements pertaining to BRCA1/2 include (not an all-inclusive list):

1. “Tumour BRCA1/2 testing should be carried out at primary diagnosis.
2. Tumour BRCA1/2 testing should be carried out at disease recurrence (if not carried out earlier)
3. Germline and/or tumour BRCA testing should be used (in either order) to determine BRCA status at primary diagnosis” (Vergote et al., 2022).

References 

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2. Ambry. (2023). Ambry Genetics. https://www.ambrygen.com/providers/oncology/test-menu#breast
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4. Buchanan, A. H., Voils, C. I., Schildkraut, J. M., Fine, C., Horick, N. K., Marcom, P. K., Wiggins, K., & Skinner, C. S. (2017). Adherence to Recommended Risk Management among Unaffected Women with a BRCA Mutation. J Genet Couns, 26(1), 79-92. https://doi.org/10.1007/s10897-016-9981-6
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10. Konstantinopoulos, P. A., Norquist, B., Lacchetti, C., Armstrong, D., Grisham, R. N., Goodfellow, P. J., Kohn, E. C., Levine, D. A., Liu, J. F., Lu, K. H., Sparacio, D., & Annunziata, C. M. (2020). Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer: ASCO Guideline. Journal of Clinical Oncology, JCO.19.02960. https://doi.org/10.1200/JCO.19.02960
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13. Manahan, E. R., Kuerer, H. M., Sebastian, M., Hughes, K. S., Boughey, J. C., Euhus, D. M., Boolbol, S. K., & Taylor, W. A. (2019). Consensus Guidelines on Genetic Testing for Hereditary Breast Cancer from the American Society of Breast Surgeons. Ann Surg Oncol, 26(10), 3025-3031. https://doi.org/10.1245/s10434-019-07549-8
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15. Meric-Bernstam, F., Gutierrez-Barrera, A. M., Litton, J., Mellor-Crummey, L., Ready, K., Gonzalez-Angulo, A. M., Lu, K. H., Hortobagyi, G. N., & Arun, B. K. (2013). Genotype in BRCA-associated breast cancers. Breast J, 19(1), 87-91. https://doi.org/10.1111/tbj.12056
16. Moyer, V. A. (2014). Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med, 160(4), 271-281. https://doi.org/10.7326/m13-2747
17. Myriad Genetics, I. (2024). What is Myriad myChoice® CDx? Myriad Genetics, Inc. Retrieved 4/4/2024 from https://myriad.com/products-services/precision-medicine/mychoice-cdx/
18. NCCN. (2024a, March 11, 2024). Breast Cancer, Version 2.2024. Retrieved 4/4/2024 from https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
19. NCCN. (2024b, February 12, 2024). Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Version 3.2024. NCCN. Retrieved 4/4/2024 from https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf
20. NCCN. (2024c, May 13, 2024). Ovarian Cancer Including Fallopian Tube Cancer and Peritoneal Cancer Version 2.2024 — May 13, 2024. NCCN. Retrieved 4/4/2024 from https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf
21. NCCN. (2024d, April 30, 2024). Pancreatic adenocarcinoma Version 2.2024 — April 30, 2024. Retrieved 4/4/2024 from https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
22. NCCN. (2024e, May 17, 2024). Prostate Cancer Version 4.2024 — May 17, 2024. NCCN. Retrieved 4/4/2024 from https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
23. NICE. (2019). Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer. https://www.nice.org.uk/guidance/cg164/chapter/Recommendations#genetic-testing
24. Palmer, J. R., Polley, E. C., Hu, C., John, E. M., Haiman, C., Hart, S. N., Gaudet, M., Pal, T., Anton-Culver, H., Trentham-Dietz, A., Bernstein, L., Ambrosone, C. B., Bandera, E. V., Bertrand, K. A., Bethea, T. N., Gao, C., Gnanaolivu, R. D., Huang, H., Lee, K. Y., . . . Couch, F. J. (2020). Contribution of Germline Predisposition Gene Mutations to Breast Cancer Risk in African American Women. J Natl Cancer Inst, 112(12), 1213-1221. https://doi.org/10.1093/jnci/djaa040
25. Pan, Z., & Xie, X. (2017). BRCA mutations in the manifestation and treatment of ovarian cancer. Oncotarget, 8(57), 97657-97670. https://doi.org/10.18632/oncotarget.18280
26. Paul, A., & Paul, S. (2014). The breast cancer susceptibility genes (BRCA) in breast and ovarian cancers. Front Biosci (Landmark Ed), 19, 605-618. https://doi.org/10.2741%2F4230
27. Petrucelli, N., Daly, M., & Pal, T. (2016). BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer [Text]. https://pubmed.ncbi.nlm.nih.gov/20301425/
28. Roy, R., Chun, J., & Powell, S. N. (2012). BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer, 12(1), 68-78. https://doi.org/10.1038/nrc3181
29. Singer, C. F., Balmaña, J., Bürki, N., Delaloge, S., Filieri, M. E., Gerdes, A.-M., Grindedal, E. M., Han, S., Johansson, O., Kaufman, B., Krajc, M., Loman, N., Olah, E., Paluch-Shimon, S., Plavetic, N. D., Pohlodek, K., Rhiem, K., Teixeira, M., & Evans, D. G. (2019). Genetic counselling and testing of susceptibility genes for therapeutic decision-making in breast cancer&#x2014;an European consensus statement and expert recommendations. European Journal of Cancer, 106, 54-60. https://doi.org/10.1016/j.ejca.2018.10.007
30. Tew, W. P., Lacchetti, C., Ellis, A., Maxian, K., Banerjee, S., Bookman, M., Jones, M. B., Lee, J. M., Lheureux, S., Liu, J. F., Moore, K. N., Muller, C., Rodriguez, P., Walsh, C., Westin, S. N., & Kohn, E. C. (2020). PARP Inhibitors in the Management of Ovarian Cancer: ASCO Guideline. J Clin Oncol, 38(30), 3468-3493. https://doi.org/10.1200/jco.20.01924
31. Tomao, F., Musacchio, L., Di Mauro, F., Boccia, S. M., Di Donato, V., Giancotti, A., Perniola, G., Palaia, I., Muzii, L., & Benedetti Panici, P. (2019). Is BRCA mutational status a predictor of platinum-based chemotherapy related hematologic toxicity in high-grade serous ovarian cancer patients? Gynecol Oncol, 154(1), 138-143. https://doi.org/10.1016/j.ygyno.2019.04.009
32. USPSTF. (2019, August 20). BRCA-Related Cancer: Risk Assessment, Genetic Counseling, and Genetic Testing. Retrieved 02/27/2019 from https://www.uspreventiveservicestaskforce.org/uspstf/document/RecommendationStatementFinal/brca-related-cancer-risk-assessment-genetic-counseling-and-genetic-testing
33. Vergote, I., González-Martín, A., Ray-Coquard, I., Harter, P., Colombo, N., Pujol, P., Lorusso, D., Mirza, M. R., Brasiuniene, B., Madry, R., Brenton, J. D., Ausems, M. G. E. M., Büttner, R., Lambrechts, D., Vergote, I., Ausems, M., Brasiuniene, B., Brenton, J., Büttner, R., . . . Witteveen, E. (2022). European experts consensus: BRCA/homologous recombination deficiency testing in first-line ovarian cancer. Annals of Oncology, 33(3), 276-287. https://doi.org/10.1016/j.annonc.2021.11.013
34. Walsh, C. S. (2015). Two decades beyond BRCA1/2: Homologous recombination, hereditary cancer risk and a target for ovarian cancer therapy. Gynecol Oncol, 137(2), 343-350. https://doi.org/10.1016/j.ygyno.2015.02.017
35. Yoo, J., Lee, G. D., Kim, J. H., Lee, S. N., Chae, H., Han, E., Kim, Y., & Kim, M. (2020). Clinical Validity of Next-Generation Sequencing Multi-Gene Panel Testing for Detecting Pathogenic Variants in Patients With Hereditary Breast-Ovarian Cancer Syndrome. Ann Lab Med, 40(2), 148-154. https://doi.org/10.3343/alm.2020.40.2.148
36. Yoshida, K., & Miki, Y. (2004). Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci, 95(11), 866-871. https://pubmed.ncbi.nlm.nih.gov/15546503/

Code Section

Code	Number	Description
CPT	81162	BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (e.g., hereditary breast and ovarian cancer) gene analysis; full sequence analysis and full duplication/deletion analysis (i.e., detection of large gene rearrangements)
	81163	BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (e.g., hereditary breast and ovarian cancer) gene analysis; full sequence analysis
	81164	BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (e.g., hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (i.e., detection of large gene rearrangements)
	81165	BRCA1 (BRCA1, DNA repair associated) (e.g., hereditary breast and ovarian cancer) gene analysis; full sequence analysis
	81166	BRCA1 (BRCA1, DNA repair associated) (e.g., hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (i.e., detection of large gene rearrangements)
	81167	BRCA2 (BRCA2, DNA repair associated) (e.g., hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (i.e., detection of large gene rearrangements)
	81212	BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (e.g., hereditary breast and ovarian cancer) gene analysis; 185delAG, 5385insC, 6174delT variants
	81215	BRCA1 (BRCA1, DNA repair associated) (e.g., hereditary breast and ovarian cancer) gene analysis; known familial variant
	81216	BRCA2 (BRCA2, DNA repair associated) (e.g., hereditary breast and ovarian cancer) gene analysis; full sequence analysis
	81217	BRCA2 (BRCA2, DNA repair associated) (e.g., hereditary breast and ovarian cancer) gene analysis; known familial variant
	81432	Hereditary breast cancer-related disorders (e.g., hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); genomic sequence analysis panel, must include sequencing of at least 10 genes, always including BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6, PALB2, PTEN, STK11, and TP53
	81433	Hereditary breast cancer-related disorders (e.g., hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); duplication/deletion analysis panel, must include analyses for BRCA1, BRCA2, MLH1, MSH2, and STK11
	81479	Unlisted molecular pathology procedure
	0102U	Hereditary breast cancer-related disorders (e.g., 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]) Proprietary test: BreastNext® Lab/Manufacturer: Ambry Genetics®
	0103U	Hereditary ovarian cancer (e.g., 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 (24 genes [sequencing and deletion/duplication], EPCAM [deletion/duplication only]) Proprietary test: OvaNext® Lab/Manufacturer: Ambry Genetics®
	0129U	Hereditary breast cancer–related disorders (e.g., 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) Proprietary test: BRCAplus Lab/Manufacturer: Ambry Genetics
	0172U	Oncology (solid tumor as indicated by the label), somatic mutation analysis of BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) and analysis of homologous recombination deficiency pathways, DNA, formalin-fixed paraffin-embedded tissue, algorithm quantifying tumor genomic instability score Proprietary test: myChoice® CDx Lab/Manufacturer: Myriad Genetics Laboratories Inc.
	0474U (effective 07/01/2024)	Hereditary pan-cancer (e.g., hereditary sarcomas, hereditary endocrine tumors, hereditary neuroendocrine tumors, hereditary cutaneous melanoma), genomic sequence analysis panel of 88 genes with 20 duplications/deletions using next generation sequencing (NGS), Sanger sequencing, blood or saliva, reported as positive or negative for germline variants, each gene Proprietary test: GeneticsNow® Comprehensive Germline Panel Lab/Manufacturer: GoPath Diagnostics Inc., GoPath Diagnostics Inc.
	0475U (effective 07/01/2021)	Hereditary prostate cancer related disorders, genomic sequence analysis panel using next-generation sequencing (NGS), Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), and array comparative genomic hybridization (CGH), evaluation of 23 genes and duplications/deletions when indicated, pathologic mutations reported with a genetic risk score for prostate cancer Proprietary test: ProstateNowTM Prostate Germline Panel Lab/Manufacturer: GoPath Diagnostics Inc., GoPath Diagnostics Inc.

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2024 Forward     

08/22/2024 Annual review, updating coverage criteria #4, adding coverage criteria #7, updating notes #1,#2,#3. Also updating description, rationale, and references

06/26/2024 Interim review to add PLA codes 0474U and 0475U to coding section.

01012024  NEW POLICY