Download genetic testing for hereditary breast and/or ovarian cancer syndrome

GENETIC TESTING FOR HEREDITARY BREAST
AND/OR OVARIAN CANCER SYNDROME (HBOC)
Protocol: GEN002
Effective Date: January 1, 2017
Table of Contents
Page
COMMERCIAL COVERAGE RATIONALE......................................................................................... 1
MEDICARE COVERAGE RATIONALE ............................................................................................... 5
MEDICAID COVERAGE RATIONALE .............................................................................................. 11
DESCRIPTION OF SERVICES ............................................................................................................ 13
CLINICAL EVIDENCE ......................................................................................................................... 13
U.S. FOOD AND DRUG ADMINISTRATION (FDA) ........................................................................ 17
APPLICABLE CODES .......................................................................................................................... 17
REFERENCES ....................................................................................................................................... 18
PROTOCOL HISTORY/REVISION INFORMATION ........................................................................ 21
INSTRUCTIONS FOR USE
This protocol provides assistance in interpreting UnitedHealthcare benefit plans. When deciding
coverage, the enrollee specific document must be referenced. The terms of an enrollee's document
(e.g., Certificate of Coverage (COC) or Evidence of Coverage (EOC)) may differ greatly. In the event
of a conflict, the enrollee's specific benefit document supersedes this protocol. All reviewers must first
identify enrollee eligibility, any federal or state regulatory requirements and the plan benefit coverage
prior to use of this Protocol. Other Protocols, Policies and Coverage Determination Guidelines may
apply. UnitedHealthcare reserves the right, in its sole discretion, to modify its Protocols, Policies and
Guidelines as necessary. This protocol is provided for informational purposes. It does not constitute
medical advice. This policy does not govern Medicare Group Retiree members.
UnitedHealthcare may also use tools developed by third parties, such as the MCG™ Care Guidelines,
to assist us in administering health benefits. The MCG™ Care Guidelines are intended to be used in
connection with the independent professional medical judgment of a qualified health care provider and
do not constitute the practice of medicine or medical advice.
COMMERCIAL COVERAGE RATIONALE
This protocol discusses genetic testing for hereditary breast and/or ovarian cancer (HBOC) syndrome
otherwise known as BRCA1 and BRCA2.
Definitions
Please note, for the purpose of this policy:
 Close blood relatives are defined as follows:
o First degree relatives include parents, siblings and offspring
o Second degree relatives include half-brothers/sisters, aunts/uncles, grandparents, grandchildren
and nieces/nephews affected on the same side of the family
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o Third degree relatives include first cousins, great-aunts/uncles, great-grandchildren and great
grandparents affected on same side of family
A breast cancer diagnosis includes either invasive carcinomas or non-invasive (in situ) ductal
carcinoma types.
Ovarian cancer also includes fallopian tube cancers and primary peritoneal carcinoma.
Limited family history is defined as having fewer than two known first-degree or second-degree
female relatives or female relatives surviving beyond 45 years of age on either or both sides of the
family (e.g., individual who is adopted).
Documentation of personal and family history, in the form of a pedigree drawing/diagram utilizing
standardized nomenclature, should be in the contemporaneous medical records submitted with the
testing request (i.e., request form).
For the statements that include age guidelines, a person is considered to be 45 years of age up until
the day before their 46th birthday, and a person is considered to be 50 years of age up until the day
before their 51st birthday.
Two breast primary cancers include cancers appearing at the same time (synchronous) and one is
not a metastasis of the other; or primary cancers developing at different times (metachronous or
asynchronous). The tumors may be in one or two breasts.
Gleason scoring is a system of grading prostate cancer tissue based on how it looks under a
microscope. Gleason scores range from 2 to 10 and indicate how likely it is that a tumor will
spread. A low Gleason score means the cancer tissue is similar to normal prostate tissue and the
tumor is less likely to spread. A high Gleason score means the cancer tissue is very different from
normal and the tumor is more likely to spread.
HBOC-associated malignancies include prostate cancer (Gleason score ≥7), pancreatic cancer or
melanoma. The presence of these malignancies does not necessarily justify BRCA testing. For
example, a female with breast cancer over age 50 whose sister had melanoma at 40 and whose
father has prostate cancer (Gleason score ≥7) would meet criteria. In another example, a female
with breast cancer over age 50 whose maternal aunt had pancreatic cancer and whose paternal
uncle had prostate cancer (Gleason score ≥7) would not meet criteria because the aunt and uncle
are on different sides of the family.
Triple-negative breast cancer refers to any breast cancer that does not show expression of estrogen
receptors (ER), progesterone receptors (PR) or HER2/neu. This subtype of breast cancer is
clinically characterized as more aggressive and less responsive to standard treatment and is
associated with poorer overall patient prognosis. It is diagnosed more frequently in younger
women, women with BRCA1 mutations and those belonging to African-American and Hispanic
ethnic groups.
A founder mutation is a gene mutation observed with high frequency in a group that is or was
geographically or culturally isolated, in which one or more of the ancestors was a carrier of the
mutant gene. This phenomenon is often called a founder effect (National Cancer Institute website).
Genetic Counseling
Genetic counseling is required by an independent (not employed by a genetic testing lab) genetics
provider prior to genetic testing for BRCA mutations in order to inform persons being tested about the
benefits and limitations of a specific genetic test as applied to a unique person. Genetics providers
employed by or contracted with a laboratory that are part of an integrated health system that routinely
delivers health care services beyond the laboratory testing itself are considered independent. Genetic
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testing for BRCA mutations requires documentation of medical necessity by ONE of the following
who has evaluated the member and intends to engage in post- test follow-up counseling:
 Board-Eligible or Board-Certified Genetic Counselor (CGC)
 Advanced Genetics Nurse (AGN-BC)
 Genetic Clinical Nurse (GCN)
 Advanced Practice Nurse in Genetics (APNG)
 A Board-Eligible or Board-Certified Clinical Geneticist
 A physician with experience in cancer genetics (Defined as providing cancer risk assessment on a
regular basis and having received specialized ongoing training in cancer genetics. Educational
seminars offered by commercial laboratories about how to perform genetic testing are not
considered adequate training for cancer risk assessment and genetic counseling.)
Documentation requirements:
 Three generation pedigree
 Genetic counseling attestation form.
BRCA Testing Criteria
Note: National Comprehensive Cancer Network (NCCN) guidelines state that meeting one or more of
these criteria warrants further personalized risk assessment, genetic counseling and consideration of
genetic testing.
Comprehensive BRCA1/BRCA2 genetic testing includes sequencing of both BRCA1 and BRCA2
genes and analysis for large genomic rearrangements, either concurrently or sequentially. NCCN
guidelines emphasize the need for comprehensive testing for individuals who meet the testing criteria
for BRCA1/BRCA2 and have no known familial BRCA1/BRCA2 mutations who have undergone
accurate risk assessment and genetic counseling.
Personal History of Cancer
Personal History of Breast Cancer
BRCA1 and BRCA2 testing is medically necessary for women with a personal history of breast
cancer in the following situations and where gene testing results will impact medical
management:
 Breast cancer diagnosed at age 45 or younger with or without family history; OR
 Breast cancer diagnosed at age 50 or younger with:
o An additional primary breast cancer; or
o At least one close blood relative with breast cancer at any age; OR
o At least one close blood relative with pancreatic cancer; OR
o At least one close blood relative with prostate cancer (Gleason score ≥7); OR
o An unknown or limited family history (see Definitions section for further clarification of
limited family history).
 Breast cancer diagnosed at any age with:
o At least one close blood relative with breast cancer diagnosed at age 50 or younger; OR
o At least two close blood relatives on the same side of the family with breast cancer at any age;
OR
o At least one close blood relative with ovarian cancer at any age; OR
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o At least two close blood relatives on the same side of the family with pancreatic and/or prostate
cancer (Gleason score ≥7) at any age; OR
o Close male blood relative with breast cancer; OR
o At least one close blood relative who has a BRCA1 or BRCA2 mutation (Testing should be
targeted to the known BRCA1/BRCA2 mutation in the family. Further BRCA1/BRCA2 testing
should only be pursued if the results are negative and the patient otherwise meets testing
criteria); OR
o Ashkenazi Jewish or ethnic groups associated with founder mutations. Testing for Ashkenazi
Jewish founder-specific mutations should be performed first. Further BRCA1/BRCA2 testing
should only be pursued if the results are negative and the patient otherwise meets testing
criteria without considering Ashkenazi Jewish ancestry.
Triple-negative breast cancer diagnosed at age 60 or younger.
BRCA1 and BRCA2 testing is medically necessary for men with a personal history of breast
cancer.
BRCA1 and BRCA2 testing is medically necessary for women with a personal history of ovarian
cancer.
Personal History of Pancreatic Cancer
BRCA1 and BRCA2 testing is medically necessary for women and men with a personal history
of pancreatic cancer at any age and at least one close blood relative on the same side of the family
with ovarian cancer at any age or breast cancer (≤ age 50 years) or two relatives with breast, pancreatic
and/or prostate cancer (Gleason score ≥7) at any age.
BRCA1 and BRCA2 testing for Ashkenazi Jewish founder-specific mutations is medically
necessary for women and men with a personal history of pancreatic cancer and Ashkenazi
Jewish ancestry.
Personal History of Prostate Cancer
BRCA1 and BRCA2 testing is medically necessary for men with a personal history of prostate
cancer (Gleason score ≥ 7) at any age and at least one close blood relative on the same side of the
family with ovarian cancer at any age or breast cancer (≤ age 50 years) or two relatives with breast,
pancreatic and/or prostate cancer (Gleason score ≥ 7) at any age.
No Personal History of Cancer
BRCA1 and BRCA2 screening tests are medically necessary for men and women without a
personal history of breast or ovarian cancer with at least one of the following familial risk factors:
 At least one first- or second-degree blood relative meeting any of the criteria under Personal
History of Cancer above; OR
 At least one third-degree blood relative with breast cancer and/or ovarian cancer who has at least 2
close blood relatives with breast cancer (at least one with breast cancer at age 50 or younger)
and/or ovarian cancer; OR
 A known BRCA1/BRCA2 mutation in a blood relative (defined as first-, second- or third-degree
relative). Testing should be targeted to the known BRCA1/BRCA2 mutation in the family. Further
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BRCA1/BRCA2 testing should only be pursued if the results are negative and the patient otherwise
meets testing criteria.
NOTE: NCCN guidelines state that significant limitations of interpreting test results for an individual
without a cancer diagnosis should be discussed. If there are no living family members with breast or
ovarian cancer available for testing, consider testing family members affected with other cancers
associated with BRCA1/BRCA2, such as prostate cancer (Gleason score ≥7), pancreatic cancer or
melanoma. Testing of individuals without a cancer diagnosis should only be considered when there is
no affected family member available for testing (NCCN, 2016).
All Other Indications
 BRCA1 and/or BRCA2 testing is not medically necessary for all other indications including:
Screening for breast or ovarian cancer risk for individuals not listed in the medically necessary
indications above;
 Risk assessment of other cancers.
Further evidence is needed to establish the clinical utility of testing in other populations.
MEDICARE COVERAGE RATIONALE
Medicare does not have a National Coverage Determination (NCD) for genetic testing for hereditary
breast and/or ovarian cancer (HBOC) syndrome. There is a Local Coverage Determination (LCDs) for
Nevada for MoIDX BRCA1 and BRCA2 Genetic Testing (L36161). Accessed November 2016.
MolDX: BRCA1 and BRCA2 Genetic Testing (L36161)
Indications and Limitations of Coverage
Nationally Covered Indications
This policy covers testing for the BRCA 1 and BRCA 2 genes for patients suspected of hereditary
breast and/or ovarian cancer syndromes. To be eligible for Medicare coverage, the individual being
tested must have signs or symptoms of breast (invasive or ductal carcinoma in situ (DCIS) and/or
ovarian cancer, or must have a personal history of another cancer. Genetic testing for a known
mutation in a family is a covered service for individuals with signs and/or symptoms of breast cancer.
Testing of an unaffected Medicare eligible individual or family member is not a covered Medicare
benefit.
BRCA 1 and BRCA 2 testing consists of full sequence and duplication/deletion analysis. Genetic
testing for a known mutation in a family may be limited to the known familial variant.
The following indications for BRCA 1 and BRCA 2 testing are covered by Medicare:
Personal history of breast cancer and one or more of the following indications:
 Diagnosed ≤45 y;
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Diagnosed ≤50 y with:
o An additional breast cancer primary;
o ≥ close blood relative* with breast cancer at any age;
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o ≥1 close relative with pancreatic cancer;
o ≥1 relative with prostate cancer (Gleason score ≥7);
o An unknown or limited family history;
Diagnosed ≤ 60y with a:
o Triple negative breast cancer (estrogen receptor (ER) negative, progesterone receptor (PR)
negative, and human epidermal growth factor receptor 2 (HER2) negative);
Diagnosed at any age with:
o ≥1 close blood relatives* with breast cancer diagnosed ≤ 50y;
o ≥2 close blood relative* with breast cancer at any age;
o ≥1 close blood relative* with invasive ovarian cancer (includes fallopian tube and primary
peritoneal cancer);
o ≥2 close blood relatives* with pancreatic cancer or prostate cancer (Gleason score ≥7) at
any age;
o Close male blood relative* with breast cancer;
o Individual of ethnicity associated with higher mutation frequency (e.g. Ashkenazi Jewish);
*NCCN defines blood relative as first- (parents, siblings and children), second- (grandparents, aunts,
uncles, nieces and nephews, grandchildren and half-siblings), and third degree-relatives (greatgrandparents, great-aunts, great uncles, great grandchildren and first cousins) on same side of family.
**Includes fallopian tube, and primary peritoneal cancers. BRCA-related ovarian cancers are
associated with epithelial non-mucinous histology.
Personal history of other cancers:
 Personal history of invasive ovarian** cancer;
 Personal history of male breast cancer;
 Personal history of prostate cancer Gleason score ≥7 at any age, with ≤1 close blood relative*
with breast (≤50 y), and/or invasive ovarian, pancreatic, or prostate cancer (Gleason score ≥7)
at any age;
 Personal history of pancreatic cancer at any age with ≥1 close blood relative with breast (≤50 y)
and/or invasive ovarian and/or pancreatic cancer at any age;
 Personal history of pancreatic cancer and Ashkenazi Jewish ancestry;
Medicare will cover BRCA-testing for an adopted individual with breast or ovarian cancer diagnosed
≤45 y or ≤60 y with triple negative breast cancer, or has a personal history of an "other" cancer (see
above) that is suspicious of being a BRCA-related cancer. Individuals with little known family health
history, come from small families, and in the case of sex-specific conditions, have few female/male
relatives at risk of developing a particular condition, may also be eligible for BRCA gene testing.
Similar to all testing, these situations require explanation of medical necessity for BRCA testing in the
patient's medical record, and documentation of genetic counseling prior to BRCA testing.
Multigene Panels***
BRCA1 and BRCA2 genetic testing for susceptibility to breast or ovarian cancer with multi--gene next
-generation sequencing (NGS) panels is covered as medically necessary when ALL of the following
criteria are met:
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Pre-test genetic counseling by a cancer genetics professional has been performed and post-test
genetic counseling by a cancer genetics professional meeting NCCN accreditation criteria is
planned;
All genes in the panel are relevant to the personal and family history for the individual being
tested (panels with genes that are not relevant to the individual’s personal and family history
are not reasonable and necessary);
Criteria listed under "Personal History of Female Breast Cancer" and/or "Personal History of
Other Cancer" are met.
Individual also meets criteria for at least ONE hereditary cancer syndrome for which NCCN
guidelines provide clear testing criteria and management recommendations, including but not
limited to HBOC, Li-Fraumeni Syndrome, Cowden Syndrome, or Lynch Syndrome.
*** While not required for payment, NCCN Guidelines recommend referral to a cancer genetics
professional with expertise and experience in cancer genetics prior to genetic testing and after genetic
testing. Examples of cancer genetics professionals with expertise and experience in cancer genetics
include: an American Board of Medical Genetics or American Board of Genetic Counseling - certified
or board eligible Clinical Geneticist, Medical Geneticist or Genetic Counselor not employed by a
commercial genetic testing laboratory (excludes individuals employed by or contracted with a
laboratory that is part of an Integrated Health System which routinely delivers health care services
beyond just the laboratory test itself as these individuals are also considered independent); medical
oncologist, obstetrician-gynecologist or other physician trained in medical cancer genetics, a genetic
nurse credentialed as either a Genetic Clinical Nurse (GCN) or an Advanced Practice Nurse in
Genetics (APGN) by either the Genetic Nursing Credentialing Commission (GNCC) or the American
Nurses Credentialing Center (ANCC) who is not employed by a commercial genetic testing laboratory
(excludes individuals employed by or contracted with a laboratory that is part of an Integrated Health
System which routinely delivers health care services beyond just the laboratory test itself as these
individuals are also considered independent).
Limitations
BRCA testing is limited to once-in-a-lifetime. If a patient has been previously tested for BRCA1 and
BRCA2, repeat testing prior to Lynparza therapy is not reasonable and necessary and will not be
covered by Medicare.
Nationally Non-Covered Indications
BRCA1/BRCA2 genetic testing is not reasonable and necessary, thus it is non-covered, for the
following indications:
 Genetic screening in the general population. Such testing is considered screening and is
excluded by Medicare statute. An ABN must be obtained for BRCA 1 and BRCA 2 testing for
individuals without signs and symptoms of breast, ovarian or other hereditary cancer
syndromes as indicated in this policy.
 Testing of individuals with no personal history of breast, ovarian, fallopian tube, primary
peritoneal, pancreatic, or prostate cancer. Such testing is considered screening and is excluded
by Medicare statute. An ABN must be obtained for BRCA 1 and BRCA 2 testing for
individuals without signs and symptoms of breast, ovarian or other hereditary cancer
syndromes as indicated in this policy
 Testing of individuals under 18 years of age.
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Background
General Overview
Cancer is the result of genetic alterations that often result in the deregulation of pathways that are
important for various cellular functions including growth, maintenance of DNA integrity, cell cycle
progression, and apoptosis (programmed cell death), among others. Among women in the United
States, breast cancer is the most common cancer diagnosis, excluding squamous and basal cell skin
cancers. Breast cancer is the second leading cause of cancer deaths among women, after lung cancer.
Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States
and the fifth most common cause of cancer mortality in women. Epithelial ovarian cancer comprises
the majority of malignant ovarian neoplasms.
While most breast cancers are considered sporadic, up to 10% are due to specific mutations in single
genes that are passed down in families. Similar rates are reported for ovarian cancer. 20 Specific
patterns of breast and ovarian cancer are linked to the BRCA1 and BRCA2 genes, which cause
hereditary breast and ovarian cancer syndrome HBOC. HBOC is an inherited cancer--susceptibility
syndrome characterized by the following:
 Multiple HBOC--related cancers within a family (i.e. invasive ductal carcinoma, ductal
carcinoma in situ, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer,
melanoma, prostate cancer with Gleason score ≥7, pancreatic cancer and melanoma);
 Cancers typically occur at an earlier age than in sporadic cases (i.e., cancers not associated with
inherited genetic risk);
 Two or more primary cancers in a single individual. This could be multiple primary cancers of
the same type (e.g., bilateral breast cancer) or primary cancers of different types related to
HBOC (e.g., breast and ovarian);
 Cases of male breast cancer.
In addition, there are some histopathologic features that have been noted to occur more frequently in
breast cancers that are associated with BRCA1 or BRCA2 mutations. Multiple studies have
demonstrated that BRCA1 breast cancer is more likely to be characterized as estrogen receptor (ER)
negative, progesterone receptor (PR) negative, and human epidermal growth factor receptor 2 (HER2)
negative, also referred to as triple negative breast cancer. Studies indicate BRCA1 mutations are
identified in 9% to 28% of patients with triple negative breast cancer.
Recently, germline genetic testing of BRCA1 and BRCA2 has been shown to be informative for
treatment considerations in patients with ovarian cancer.2 Specifically, Lynparza, a poly (ADP--ribose)
polymerase (PARP) inhibitor has been FDA- approved for use as monotherapy in patients with ovarian
cancer and with deleterious or suspected deleterious germline BRCA1or BRCA2 mutation, who have
been treated with three or more prior lines of chemotherapy.
BRCA1 and BRCA2 Testing Overview
Germline genetic testing of BRCA1 and BRCA2 is available to identify individuals at increased risk
for breast and ovarian cancers, as individuals with an inherited cancer syndrome may benefit from
screening and prevention strategies to reduce their risk. The prevalence of BRCA mutations in the
population is estimated between 1 in 300 and 1 in 800; however, specific mutations known as “founder
mutations” occur more often in populations founded by a small ancestral group, including Ashkenazi
(Eastern European) Jews, French Canadians, and Icelanders. The prevalence of BRCA mutations in the
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Ashkenazi Jewish population is approximately 1 in 40. Three recurrent BRCA1 and BRCA2 mutations
have been identified in Ashkenazi Jewish individuals (i.e., a genetically distinct population of Jewish
people of eastern and central European ancestry) and make up the vast majority of BRCA mutations
that occur in this population.
Rearrangements, such as large genomic alterations including translocations, inversions, large deletions
and insertions are believed to be responsible for 12% to 18% of BRCA1 inactivating mutations but are
less common in BRCA2 and in individuals of Ashkenazi Jewish descent. The NCCN guidelines note
that comprehensive genetic testing includes full sequencing of BRCA1/BRCA2 and the detection of
large genomic rearrangements. The NCCN recommends that since certain large genomic
rearrangements are not detectable by a primary sequencing assay, additional testing may be needed in
some cases.20
Evidence in the published, peer--reviewed scientific literature indicates that BRCA1 and BRCA2
genetic testing is appropriate for a specific subset of adult individuals who have been identified to be at
high risk for hereditary breast and ovarian cancers. Furthermore, several specialty organizations,
including NCCN, American College of Medical Genetics (ACMG), and American Society of Clinical
Oncology (ASCO), have issued statements recognizing the role of pre- and post-test genetic counseling
and BRCA testing in the management of at--risk patients. The U.S. Preventive Services Task Force
(USPSTF) has published recommendations regarding genetic risk assessment, genetic counseling and
BRCA mutation testing for breast and ovarian cancer susceptibility. Based on this USPSTF
recommendation, the Patient Protection and Affordable Care Act requires that private group and
individual health plans provide coverage for genetic counseling and, if appropriate, genetic testing for
women at risk for HBOC as a preventive service with no out--of--pocket expense.
Olaparib is a poly ADP-ribose polymerase (PARP) inhibitor approved by the FDA as monotherapy in
patients with ovarian cancer, with deleterious or suspected deleterious germline BRCA1 or BRCA2
mutation who have been treated with three or more prior lines of chemotherapy. Testing of ovarian
cancer patients in this clinical scenario is indicated to guide treatment.
Mutations in the BRCA1 and BRCA2 genes are passed down in families through an autosomal
dominant inheritance pattern meaning that the associated cancer predisposition can be inherited
through either the mother’s or father’s side of the family and transmitted by a male or female. When a
parent carries a BRCA mutation, there is a 50% chance of passing down the gene mutation with every
pregnancy. Although the risk of inheriting the predisposition from a parent who carries a mutation is
50%, not everyone with an inherited mutation will develop cancer. The likelihood that a woman with a
mutation will develop a related cancer (i.e., penetrance of a BRCA mutation) is estimated between
41% and 90% and is much lower for men. The risk of developing cancer depends on numerous
variables, including the penetrance of the specific mutation, the genetic makeup of the individual,
environmental risk factors, the gender of the individual and their age.
Several national evidence--based and expert opinion guidelines and accrediting bodies recommend that
genetic testing should be undertaken only in conjunction with independent pretest genetic counseling
services in order to assist patients in complex clinical decision -making. Post--genetic testing
counseling is also strongly recommended. The NCCN guidelines [2015] state that genetic counseling is
a critical component of the cancer risk assessment process. In addition, the guidelines state that pre-test
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counseling should include a discussion of why the test is being offered and how test results may impact
medical management, cancer risks associated with the genes being tested, the significance of possible
test results for the individual and family, the likelihood of a positive result, technical aspects and
accuracy of the test, and economic considerations. Per the guidelines, post-test counseling includes
disclosure of results, discussion of the significance of the results for the individual and relevant family
members, a discussion of the impact of the results on psychosocial aspects and on the medical
management of the individual, and how and where the patient will receive follow--up care and access
to additional resources.
Medicare is a defined benefit program and requires that testing is only performed on patients with
signs and symptoms of disease. Testing of unaffected individuals or family members is not a covered
Medicare service. However, once a mutation is identified in the family, Medicare eligible relatives
with signs and symptoms of breast cancer are typically tested for that specific mutation only. For
patients of Ashkenazi Jewish descent, initial testing is generally done for the three specific mutations
that account for most hereditary breast and ovarian cancer in that population: 185delAG and 5382insC
(also called 5385insC) in the BRCA1 gene and 6174delT in the BRCA2 gene. If the test results are
negative, full analysis of the BRCA1 and BRCA2 genes is only considered if testing criteria for non-Jewish individuals are met. Nonetheless, Medicare does not cover testing for patients without signs and
symptoms of breast or ovarian cancer.
Multi-gene Panel Testing
Multi-gene panels for hereditary ovarian and breast cancer (HBOC) syndromes are available. In
general, these panels test simultaneously for several genes associated with inherited breast and/or
ovarian cancer, including but not limited to the BRCA1 and BRCA2 genes. The genes included and the
methods used in multi-gene panels vary by laboratory. Some cancer susceptibility testing panels
include genes that have not been associated with hereditary breast or ovarian cancer and, in some
cases, are not clinically actionable. Testing with a targeted panel may be indicated as a cost effective
strategy when the individual’s symptoms or family history meet testing criteria for more than one
hereditary cancer syndrome. All genes included in the test should be relevant to the personal and
family history for the individual being tested.
Test Results and Management
A positive BRCA test result reveals the presence of a mutation in either the BRCA1 or BRCA2 gene
that prevents the translation of the full--sized protein or that is known to interfere with protein function
in other ways and is associated with increased cancer risks.
Several strategies have been proposed for achieving the goal of reducing cancer risk for individuals
with known BRCA mutations. The NCCN guidelines include detailed strategies and evidence review
for at--risk patients.20 For women these strategies include breast self--exams (BSE), clinical breast
exams (CBE), mammograms, breast magnetic resonance imaging (MRI), risk--reducing bilateral
salpingo-oophorectomy, discussion of risk--reducing bilateral mastectomy, and use of trans-vaginal
ultrasound and CA-125 in women who have not elected risk--reducing ovarian surgery. For men these
include BSE and CBE starting at age 35 and consideration of mammography and prostate cancer
screening starting at age 40. For both men and women recommendations include education regarding
signs and symptoms of cancer(s), especially those associated with BRCA gene mutations, and
screening may be individualized based on cancers observed in the family.
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In patients with ovarian cancer with deleterious or suspected deleterious germline BRCA1 or BRCA2
mutation who have been treated with three or more prior lines of chemotherapy, consideration of
treatment with the PARP inhibitor Lynparza is recommended.
A negative BRCA test result is interpreted within the context of a patient's individual and family
cancer history, notably regarding whether any family member has previously been identified as
carrying a mutation or not. An affected individual who has tested negative for a BRCA mutation may
still have an inherited predisposing mutation in one of the BRCA genes that was not identified by
testing, or a mutation in another gene that predisposes to breast or ovarian cancer. An individual in
whom testing reveals they do not carry a BRCA1 or BRCA2 mutation that has been positively
identified in another family member is considered to have a true negative result (i.e., they have not
inherited the BRCA mutation nor associated increased cancer risks identified in other family
members).
A person is considered to have an indeterminate result if that person is not a carrier of a known
cancer--predisposing gene mutation and the carrier status of all other biologic family members is either
also negative or unknown. Results are considered inconclusive if the individual is a carrier of an
alteration that currently has no known clinical significance (variant of uncertain significance).
MEDICAID COVERAGE RATIONALE
BACKGROUND AND EXPLANATION
An addition to Medicaid Service Manual (MSM) Chapter 804 page 1 was made to include coverage for
Breast Cancer gene 1 (BRCA1) and Breast Cancer gene 2 (BRCA2) gene analysis in accordance with
the recommendations from the United States Preventive Services Task Force (USPSTF) and the
Affordable Care Act (ACA).
This change will be effective August 1, 2014. Accessed November 2016.
POLICY #08-01 BRCA1 / BRCA2 Gene Analysis
BRCA1/BRCA2 testing services for individuals without a personal history of breast and/or ovarian
cancer should be provided to high risk individuals as defined below, or as otherwise defined by the US
Preventive Services Task Force (USPSTF).
BRCA1/BRCA2 testing services for women with a personal history of breast and/or ovarian cancer
and for men with a personal history of breast cancer should be provided as defined below, or as
otherwise defined by the National Comprehensive Cancer Network (NCCN) Clinical Practice
Guidelines.
Genetic counseling must precede genetic testing for hereditary cancer.
If the mutation in the family is known, only the test for that mutation is covered. For example, if a
mutation for BRCA1 has been identified in a family, a single site mutation analysis for that mutation is
covered, while a full sequence BRCA1 and BRCA2 analyses is not. An exception to this can be
considered if a Certified Genetic Counselor presents sufficient justifiable need.
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If the individual is of Ashkenazi Jewish descent, test the three common mutations first. Then if
negative, consider comprehensive ("Reflex") testing based on assessment of individual and family
history as if the individual is of non-Ashkenazi Jewish descent.
COVERAGE AND LIMITATIONS:
Frequency is limited to once in a lifetime.
BRCA1/BRCA2 gene analysis is covered for individuals meeting the following criteria:
1. For individuals without diagnosis of breast or ovarian cancer:
a. Two first-degree relatives with breast cancer, one of whom was diagnosed at age 50 years or
younger;
b. A combination of three or more first- or second-degree relatives with breast cancer regardless
of age at diagnosis;
c. A combination of both breast and ovarian cancer among first- or second-degree relatives;
d. A first-degree with bilateral breast cancer;
e. A combination of two or more first- or second-degree relatives with ovarian cancer, regardless
of age at diagnosis;
f. A first or second-degree relative with both breast and ovarian cancer at any age;
g. History of breast cancer in a male relative; or
h. For women of Ashkenazi Jewish descent, any first-degree relative (or two second-degree
relatives on the same side of the family) with breast or ovarian cancer.
2. A family history of breast or ovarian cancer that includes a relative with a known deleterious BRCA
mutation; or
3. A personal history of breast cancer plus one or more of the following:
a. Diagnosed at age ≤ 45 years;
b. Diagnosed at age ≤ 50 years with ≥ 1 close blood relative with breast cancer diagnosed at any
age or with a limited family history;
c. Two breast primaries when first breast cancer occurred at age ≤ 50 years;
d. Diagnosed at age ≤ 60 years with a triple negative breast cancer;
e. Diagnosed at age ≤ 50 years with a limited family history;
f. Diagnosed at any age, with ≥ 1 close blood relative with breast cancer diagnosed ≤ 50 years;
g. Diagnosed at any age with ≥ 2 close blood relatives with breast cancer at any age;
h. Diagnosed at any age with ≥ 1 close blood relative with epithelial ovarian cancer;
i. Diagnosed at any age with ≥ 2 close blood relatives with pancreatic cancer or aggressive
prostate
j. cancer (Gleason Score ≥ 7) at any age;
k. Close male blood relative with breast cancer; or for an individual of ethnicity associated with
higher mutation frequency (e.g. Ashkenazi Jewish) no additional family history may be
required.
4. Personal history of epithelial ovarian cancer; or
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5. Personal history of male breast cancer; or
6. Personal history of pancreatic cancer or aggressive prostate cancer (Gleason Score ≥ 7) at any age
with ≥ 2 close blood relatives with breast and/or ovarian and/or pancreatic cancer or aggressive
prostate cancer(Gleason Score ≥ 7) at any age.
DESCRIPTION OF SERVICES
About 5% to 10% of breast cancer cases are thought to be genetic. A majority of hereditary breast
cancers are associated with inherited mutations in one of the breast-cancer-susceptibility genes:
BRCA1 and BRCA2. Hereditary breast and ovarian cancers cluster in families and tend to occur at
relatively young ages. Women who carry BRCA1 and BRCA2 mutations have an increased lifetime
risk of about 80% for individuals who live to age 70. In the contralateral breast, the lifetime risk of
cancer is about 40%, and for ovarian cancer, the lifetime risk is about 40% with the BRCA1 mutation
and 20% with the BRCA2 mutation. Individuals with these mutations are also at increased risk of
certain other cancers but to a lesser degree than for breast and ovarian cancer (ECRI, 2015).
According to the NCCN, comprehensive genetic testing includes full sequencing of BRCA1/BRCA2
and detection of large genomic rearrangements and may be indicated for individuals at exceptionally
high risk as determined through cancer risk assessment and counseling (NCCN, 2016).
CLINICAL EVIDENCE
A GeneReviews® chapter on hereditary breast and ovarian cancer addresses BRCA mutations and the
risk of developing certain cancers. An increased likelihood of a BRCA1 or BRCA2 mutation is
suspected on the basis of certain personal and family history characteristics and various clinical criteria
(Petrucelli et al., 2013).
In a Cochrane systematic review, Hilgart et al. (2012) evaluated the impact of cancer genetic riskassessment services on patients at risk of familial breast cancer. In this update, the authors included
five new trials, bringing the total number of included studies to eight. The included trials provided data
on 1973 participants and assessed the impact of cancer genetic risk assessment on outcomes including
perceived risk of inherited cancer, and psychological distress. The review suggests that cancer genetic
risk-assessment services help to reduce distress, improve the accuracy of the perceived risk of breast
cancer and increase knowledge about breast cancer and genetics. The review found favorable outcomes
for patients after risk assessment for familial breast cancer.
Warlam-Rodenhuis et al. (2005) completed a 1000 patient prospective study to determine predictive
factors linked to BRCA1/BRCA2. The family history of breast cancer was the highest predictive factor
of a positive BRCA test. The next highest predictive factor was age. Nearly 30% of BRCA carriers had
no family history of breast or ovarian cancer and an additional 50% of the mutation carriers had no
affected first-degree relatives with breast cancer suggesting that BRCA screening based on family
history alone would miss a considerable proportion of mutation carriers. The frequency of BRCA
mutations in patients diagnosed before the age of 45 years indicated that this age was a useful selection
criterion.
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The National Institute for Health and Care Excellence (NICE) published guidelines addressing the
classification and care of people at risk of familial breast cancer and management of breast cancer and
related risks in people with a family history of breast cancer (NICE, 2013; updated 2015).
The U.S. Preventive Services Task Force (USPSTF, 2013) recommends that primary care providers
screen women who have family members with breast, ovarian, tubal or peritoneal cancer with one of
several screening tools 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).
Women with positive screening results should receive genetic counseling and, if indicated after
counseling, BRCA testing (Grade B).
Grade B recommendation: The USPSTF recommends the service. There is high certainty that the net
benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.
The USPSTF recommends against routine genetic counseling or BRCA testing for women whose
family history is not associated with an increased risk for potentially harmful mutations in the BRCA1
or BRCA2 genes (Grade D).
Grade D recommendation: The USPSTF recommends against the service. There is moderate or high
certainty that the service has no net benefit or that the harms outweigh the benefits.
Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 have been proven to indicate a
drastically increased lifetime risk of breast and ovarian cancers in the individuals who carry them. A
number of studies have shown that the third most common cancer associated with these mutations is
pancreatic cancer (Greer and Whitcomb, 2007).
Castro et al. (2013) analyzed the tumor features and outcomes of 2,019 patients with prostate cancer
(18 BRCA1 carriers, 61 BRCA2 carriers and 1,940 noncarriers). The study reported that prostate
cancers with germline BRCA1/2 mutations were more frequently associated with Gleason ≥ 8, T3/T4
stage, nodal involvement and metastases at diagnosis than prostate cancers in noncarriers. BRCA
mutations were associated with poor survival outcomes. Cause-specific overall survival (CSS) was
significantly longer in noncarriers than in carriers. For localized prostate cancer, 5-year CSS and
metastasis-free survival (MFS) were significantly higher in noncarriers.
Of 211 Ashkenazi Jewish breast cancer probands with a family history of pancreatic cancer, Stadler et
al. (2011) found that 30 (14.2%) harbored a BRCA mutation. Fourteen (47%) of the mutations were in
BRCA1 and 16 (53%) were in BRCA2. Patients diagnosed with breast cancer at age ≤ 50 years were
found to have a higher BRCA1/2 mutation prevalence than probands with breast cancer who were
diagnosed at age > 50 years (21.1% vs 6.9%). In patients with a first-, second-, or third-degree relative
with pancreatic cancer, mutation prevalences were 15.4%, 15.3% and 8.6%, respectively. The authors
found that BRCA1 and BRCA2 mutations are observed with nearly equal distribution in Ashkenazi
Jewish breast-pancreas cancer families, suggesting that both genes are associated with pancreatic
cancer risk.
Ferrone et al. (2009) looked at the prevalence of BRCA1 and BRCA2 in an unselected group of Jewish
patients and compared patients with resected BRCA mutation-associated pancreatic adenocarcinoma
Genetic Testing for Hereditary Breast and/or Ovarian Cancer Syndrome (HBOC)
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(PAC) to PAC patients without mutations. Of the 187 Jewish patients who underwent resection for
PAC, tissue was available for 145 patients. Founder mutations for BRCA1 and BRCA2 were identified
in 5.5% of patients (two with BRCA1 [1.3%] and six with BRCA2 [4.1%]). A previous cancer was
reported by 24% (35 of 145) of patients with the most common sites being breast cancer (9 of 35;
74%) and prostate cancer (8 of 35; 23%).
Large Genomic Rearrangement (LR) Testing
The prevalence of BRCA1/2 LRs was investigated in 48,456 patients with diverse clinical histories and
ancestries that were referred for clinical molecular testing for suspicion of hereditary breast and
ovarian cancer. Prevalence data was analyzed for patients from different risk and ethnic groups.
Patients were designated as high-risk (n=25,535) if their clinical history predicted a high prior
probability. For these patients, large rearrangement (LR) testing was performed automatically in
conjunction with sequencing. Elective patients (n=22,921) did not meet the high-risk criteria, but
underwent LR testing if BRCA1/2 sequencing indicated no known mutations. Overall BRCA1/2
mutation prevalence among high-risk patients was 23.8% versus 8.2% for the elective group. The
mutation profile for high-risk patients was 90.1% sequencing mutations versus 9.9% LRs, and for
elective patients, 94.1% sequencing versus 5.9% LRs. The authors noted that this difference may
reflect the bias in high-risk patients to carry mutations in BRCA1, which has a higher penetrance and
frequency of LRs compared with BRCA2. Significant differences in the prevalence and types of LRs
were found in patients of different ancestries. LR mutations were significantly more common in Latin
American/Caribbean patients (Judkins et al., 2012).
Walsh et al., (2006) found that genetic tests used to determine risk for developing hereditary breast
cancer failed to detect BRCA1 and BRCA2 mutations in approximately 12% of breast cancer patients
(n=300) who were members of a family with at least 4 cases of breast cancer and/or ovarian cancer. In
this study, researchers retested participants for carrier status of genetic mutations known to influence
risk for development of breast cancer using a molecular method not currently cleared for market in the
United States known as multiplex ligation-dependent probe amplification (MLPA). Prior to
enrollment, all participants had received a negative result from the breast cancer genetic test (Myriad
Genetics Inc.) used routinely in the United States. The results of MLPA analysis indicated that 17% of
study participants were, in fact, carriers of breast cancer-relevant genetic mutation, with 12% found to
have alterations of BRCA1 or BRCA2. Inherited alterations of BRCA1 were more frequent among
participants who were diagnosed with breast cancer prior to 40 years of age (16%) than among those
who were older when diagnosed (6.5%). The clinical implications of these findings cannot be
generalized to other populations, but results strongly suggest that improved methods for determining
breast cancer risk are needed for individuals with strong family histories of breast and/or ovarian
cancer.
Unger et al. (2000) assessed the frequency of genomic rearrangements in BRCA1 in 42 American
families with breast and ovarian cancer who were seeking genetic testing and who were subsequently
found to be negative for BRCA1 and BRCA2 coding-region mutations. The exon 13 duplication was
detected in one family, and four families had other genomic rearrangements. A total of 5 (11. 9%) of
the 42 families with breast/ovarian cancer who did not have BRCA1 and BRCA2 coding-region
mutations had mutations in BRCA1 that were missed by conformation-sensitive gel electrophoresis or
sequencing. Four of five families with BRCA1 genomic rearrangements included at least one
individual with both breast and ovarian cancer; therefore, 4 (30.8%) of 13 families with a case of
Genetic Testing for Hereditary Breast and/or Ovarian Cancer Syndrome (HBOC)
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multiple primary breast and ovarian cancer had a genomic rearrangement in BRCA1. Families with
genomic rearrangements had prior probabilities of having a BRCA1 mutation, ranging from 33% to
97% (mean 70%). In contrast, in families without rearrangements, prior probabilities of having a
BRCA1 mutation ranged from 7% to 92% (mean 37%).
Triple-Negative Breast Cancer
A meta-analysis by Tun et al (2014) reported that a triple-negative phenotype significantly increases
the risk of having a BRCA1 mutation in high-risk breast cancer patients compared with a non-triplenegative phenotype. In a high-risk population, women with triple negative breast cancer (TNBC) are
approximately five and a half times more likely to have a BRCA1 mutation compared with a nonTNBC phenotype. Approximately two in nine women with TNBC harbor a BRCA1 mutation. Twelve
studies comprising 2533 breast cancer patients were included in the analysis.
A study of 54 women with triple-negative breast cancer aged 40 years or younger, who were not
considered candidates for BRCA testing because of the lack of a strong family history, showed five
with BRCA1 mutations and one with a BRCA2 mutation (11% mutation prevalence) (Young et al.
2009).
Several studies have shown that BRCA1 breast cancer is more likely to be characterized as triplenegative. Studies have reported BRCA1 mutations in 9-28% of patients with triple-negative breast
cancer. In addition, it appears that among patients with triple-negative disease, BRCA mutation
carriers were diagnosed at a younger age compared with non-carriers (NCCN, 2016).
In a cohort of triple-negative breast cancer patients, Gonzalez-Angulo et al. (2011) found a 19.5%
incidence of BRCA mutations. Median age was 51 years (27-83 years). The authors recommend that
genetic testing be discussed with patients with triple-negative breast cancer.
Almost 10% of women with breast cancer who are younger than age 50 have BRCA mutations. Most
of the BRCA-positive women do not have personal or family histories of breast or ovarian cancer and
are not of Ashkenazi Jewish ancestry. Using a simulation model, Kwon et al. (2010) evaluated six
populations of women younger than 50 with breast cancer, looking at costs and health benefits. The
results led the authors to conclude that testing women with triple-negative breast cancers who were
younger than 50 years for BRCA mutations should be adopted into current guidelines for genetic
testing.
NCCN guidelines present specific criteria for genetic testing for hereditary breast and/or ovarian
cancer syndrome. The guidelines address genetic risk assessment, counseling, testing and management
based on test results (NCCN, 2016).
Professional Societies
American College of Obstetricians and Gynecologists (ACOG)
In a 2009 practice bulletin (reaffirmed 2015), the ACOG recommended criteria for genetic risk
assessment of hereditary breast and ovarian cancer syndrome (HBOC). These recommendations
conclude:
 BRCA positive women should be offered salpingo-oophorectomy by age 40 or when childbearing
is completed.
Genetic Testing for Hereditary Breast and/or Ovarian Cancer Syndrome (HBOC)
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

For a risk reducing bilateral salpingo-oophorectomy, all tissue from the ovaries and fallopian tubes
should be removed. Thorough visualization of the peritoneal surfaces with pelvic washings should
be performed. Complete, serial sectioning of the ovaries and fallopian tubes is necessary, with
microscopic examination for occult cancer.
Genetic risk assessment is recommended for patients with a greater than an approximate 20-25%
chance of having an inherited predisposition to breast cancer and ovarian cancer. This includes
women with the following:
o A close relative (mother, sister, daughter, grandmother, granddaughter, aunt or niece) with a
known BRCA mutation
o Personal history of both breast and ovarian cancer
o Ovarian cancer and a close relative with ovarian cancer or premenopausal breast cancer or both
o Ovarian cancer and Ashkenazi Jewish ancestry
o Breast cancer by age 40 years and Ashkenazi Jewish ancestry
o Breast cancer by age 50 years and a close relative with ovarian cancer or male breast cancer
American Society of Clinical Oncology (ASCO)
An ASCO policy statement recommends that genetic testing for cancer susceptibility be performed
when the following three criteria are met: the individual being tested has a personal or family history
suggestive of genetic cancer susceptibility; the test can be adequately interpreted; and the test results
have accepted clinical utility (ASCO, 2003; Robson et al., 2010; Robson et al., 2015).
National Society of Genetic Counselors (NSGC)
The NSGC recommends that genetic testing be performed in the context of an informed decisionmaking process (Berliner et al., 2013). The process of cancer risk assessment and genetic counseling
for hereditary breast and ovarian cancer syndrome requires many steps, including the following:
 Gathering personal medical and family history data
 Psychosocial assessment
 Discussion of cancer and mutation risk and how personalized risk estimates are derived
 Facilitation of the informed consent process through discussion of the risks, benefits, limitations,
and likelihood of identifying a mutation with genetic susceptibility testing
 Results disclosure (if applicable)
 Discussion of medical management options
 Review of issues related to genetic discrimination
U.S. FOOD AND DRUG ADMINISTRATION (FDA)
Genetic tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA) Act of
1988. More information is available at:
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/IVDRegulatoryAssistance/ucm12
4105.htm. Accessed November 2016.
APPLICABLE CODES
The following list(s) of procedure and/or diagnosis codes is provided for reference purposes only and
may not be all inclusive. Listing of a code in this policy does not imply that the service described by
the code is a covered or non- covered health service. Benefit coverage for health services is determined
Genetic Testing for Hereditary Breast and/or Ovarian Cancer Syndrome (HBOC)
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by the member specific benefit plan document and applicable laws that may require coverage for a
specific service. The inclusion of a code does not imply any right to reimbursement or guarantee claim
payment. Other Policies and Coverage Determination Guidelines may apply.
CPT® Code
Description
BRCA1, BRCA2 (breast cancer 1 and 2) (e.g., hereditary breast and ovarian
81162
cancer) gene analysis; full sequence analysis and full duplication/deletion
analysis
BRCA1, BRCA2 (breast cancer 1 and 2) (e.g., hereditary breast and ovarian
cancer) gene analysis; full sequence analysis and common
81211
duplication/deletion variants in BRCA1 (i.e., exon 13 del 3.835kb, exon 13
dup 6kb, exon 14-20 del 26kb, exon 22 del 510bp, exon 8-9 del 7.1kb)
BRCA1, BRCA2 (breast cancer 1 and 2) (e.g., hereditary breast and ovarian
81212
cancer) gene analysis; 185delAG, 5385insC, 6174delT variants
BRCA1 (breast cancer 1) (e.g., hereditary breast and ovarian cancer) gene
analysis; full sequence analysis and common duplication/deletion variants (ie,
81214
exon 13 del 3.835kb, exon 13 dup 6kb, exon 14-20 del 26kb, exon 22 del
510bp, exon 8-9 del 7.1kb)
BRCA1 (breast cancer 1) (e.g., hereditary breast and ovarian cancer) gene
81215
analysis; known familial variant
BRCA2 (breast cancer 2) (e.g., hereditary breast and ovarian cancer) gene
81216
analysis; full sequence analysis
BRCA2 (breast cancer 2) (e.g., hereditary breast and ovarian cancer) gene
81217
analysis; known familial variant
Hereditary breast cancer-related disorders (e.g., hereditary breast cancer,
hereditary ovarian cancer, hereditary endometrial cancer); genomic sequence
81432
analysis panel, must include sequencing of at least 14 genes, including ATM,
BRCA1, BRCA2, BRIP1, CDH1, MLH1, MSH2, MSH6, NBN, PALB2,
PTEN, RAD51C, STK11, and TP53
Hereditary breast cancer-related disorders (e.g., hereditary breast cancer,
hereditary ovarian cancer, hereditary endometrial cancer);
81433
duplication/deletion analysi.s panel, must include analyses for BRCA1,
BRCA2, MLH1, MSH2, and STK11
Medical genetics and genetic counseling services, each 30 minutes
96040
face-to-face with patient/family
Large Genomic Rearrangements
BRCA1, BRCA2 (breast cancer 1 and 2) (e.g., hereditary breast and ovarian
81213
cancer) gene analysis; uncommon duplication/deletion variants
CPT® is a registered trademark of the American Medical Association.
REFERENCES
American College of Obstetricians and Gynecologists. Practice Bulletin number 103. Hereditary breast
and ovarian cancer syndrome. Obstetrics and Gynecology April 2009: 113:957-66. Reaffirmed 2013.
Genetic Testing for Hereditary Breast and/or Ovarian Cancer Syndrome (HBOC)
Page 18 of 21
American Society of Clinical Oncology. ASCO policy statement update: genetic testing for cancer
susceptibility. J Clin Oncol. 2003 Jun 15;21(12):2397-406.
Berliner JL, Fay AM, Cummings SA, et al. National Society of Genetic Counselors (NSGC) practice
guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. J Genet
Couns. 2013 Apr;22(2):155-63.
Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal
involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013
May 10;31(14):1748-57.
ECRI Institute. Genetic Test Hotline Response. BRCA1 and BRCA2 gene testing for assessing risk of
breast and ovarian cancer. March 2015.
ECRI Institute. Genetic Test Product Brief. BRACAnalysis test (Myriad Genetics, Inc.) for assessing
risk of hereditary breast and ovarian cancer. December 2014.
Ferrone CR, Levine DA, Tang LH, et al. BRCA germline mutations in Jewish patients with pancreatic
adenocarcinoma. J Clin Oncol. 2009 Jan 20;27(3):433-8.
Gonzalez-Angulo AM, Timms KM, Liu S, et al. Incidence and outcome of BRCA mutations in
unselected patients with triple receptor-negative breast cancer. Clin Cancer Res. 2011 Mar
1;17(5):1082-9.
Greer JB, Whitcomb DC. Role of BRCA1 and BRCA2 mutations in pancreatic cancer. Gut. 2007
May;56(5):601-5.
Hayes, Inc. Hayes Genetic Test Evaluation Report. Breast cancer susceptibility 1 and 2 (BRCA1/2)
gene testing for hereditary breast and ovarian cancer (HBOC). Lansdale, PA: Hayes, Inc.; August
2013. Annual review July 2015. Archived July 2015.
Hilgart JS, Coles B, Iredale R. Cancer genetic risk assessment for individuals at risk of familial breast
cancer. Cochrane Database Syst Rev. 2012 Feb 15;2:CD003721.
Judkins T, Rosenthal E, Arnell C, et al. Clinical significance of large rearrangements in BRCA1 and
BRCA2. Cancer. 2012 Nov 1;118(21):5210-6.
Kwon JS, Gutierrez-Barrera AM, Young D, et al. Expanding the criteria for BRCA mutation testing in
breast cancer survivors. J Clin Oncol. 2010 Sep 20;28(27):4214-20.
National Cancer Institute (NCI). Genetics of breast and gynecologic cancers (PDQ®). August 2015.
Available at: http://www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq. Accessed November
2016.
National Cancer Institute (NCI). NCI dictionary of cancer terms. Available at:
http://www.cancer.gov/publications/dictionaries/cancer-terms. Accessed November 2016.
Genetic Testing for Hereditary Breast and/or Ovarian Cancer Syndrome (HBOC)
Page 19 of 21
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™.
Genetic/familial high-risk assessment: breast and ovarian. V2.2016.
National Institute for Health and Care Excellence (NICE). CG164. Familial breast cancer:
classification and care of people at risk of familial breast cancer and management of breast cancer and
related risks in people with a family history of breast cancer. June 2013. Updated August 2015.
Petrucelli N, Daly MB, Feldman GL. BRCA1 and BRCA2 hereditary breast and ovarian cancer.
September 1998. Updated September 2013. In: Pagon RA, Adam MP, Ardinger HH, et al., editors.
GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from:
http://www.ncbi.nlm.nih.gov/books/NBK1247/. Accessed November 2016.
Robson ME, Bradbury AR, Arun B, et al. American Society of Clinical Oncology policy statement
update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2015 Nov 1;33(31):3660-7.
Robson ME, Storm CD, Weitzel J, et al. American Society of Clinical Oncology policy statement
update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010 Feb 10;28(5):893901.
Stadler ZK, Salo-Mullen E, Patil SM, et al. Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi
Jewish families with breast and pancreatic cancer. Cancer. 2012 Jan 15;118(2):493-9.
Tun NM, Villani G, Ong K, et al. Risk of having BRCA1 mutation in high-risk women with triplenegative breast cancer: a meta-analysis. Clin Genet. 2014 Jan;85(1):43-8.
U.S. Preventive Services Task Force (USPSTF). BRCA-related cancer: risk assessment, genetic
counseling and genetic testing. December 2013. Available at:
https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/brca-relatedcancer-risk-assessment-genetic-counseling-and-genetic-testing?ds=1&s=cancer risk assessment .
Accessed November 2016.
Unger MA, Nathanson KL, Calzone K, Antin-Ozerkis D, Shih HA, Martin AM, et al. Screening for
genomic rearrangements in families with breast and ovarian cancer identifies BRCA1 mutations
previously missed by conformation sensitive gel electrophoresis or sequencing. Am J Hum Genet.
2000;67:841-50.
Walsh T, Casadei S, Coats KH, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53
in families at high risk of breast cancer. JAMA. 2006;295 (12):1379-1388.
Warlam-Rodenhuis CC et al. A prospective study on predictive factors linked to the presence of
BRCA1 and BRCA2 mutations in breast cancer patients. European Journal of Cancer 41 (2005) 14091415.
Young SR, Pilarski RT, Donenberg T, et al. The prevalence of BRCA1 mutations among young
women with triple-negative breast cancer. BMC Cancer. 2009 Mar 19;9:86.
Genetic Testing for Hereditary Breast and/or Ovarian Cancer Syndrome (HBOC)
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PROTOCOL HISTORY/REVISION INFORMATION
Date
11/17/2016
08/25/2016
01/27/2016
11/20/2014
10/23/2014
02/27/2014
04/25/2013
01/24/2013
11/15/2012
05/24/2012
01/26/2012
10/27/2011
12/23/2010
07/22/2010
07/24/2009
Action/Description
Corporate Medical Affairs Committee
The foregoing Health Plan of Nevada/Sierra Health & Life Health Healthcare Operations protocol has
been adopted from an existing UnitedHealthcare coverage determination guideline that was researched,
developed and approved by the UnitedHealthcare Coverage Determination Committee.
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