Download Hereditary Breast and Ovarian Cancer

Hereditary Breast
and Ovarian Cancer
KNOWING WHAT TO LOOK FOR
KNOWING WHERE TO LOOK
AND KNOWING WHAT IT MEANS
Breast and ovarian cancer occurs when normal cells in the
breast or the ovary begin to grow uncontrollably, forming a
malignant tumor. Breast cancer is the most common cancer in
women, and 1 out of every 8 (12%) women will be diagnosed
with breast cancer in their lifetime. Although the disease occurs
more frequently in women, breast cancer can also occur in men.
Ovarian cancer is the ninth most common cancer among females,
occurring in 1 out of every 70 women.
While the majority of breast and ovarian cancer is sporadic
(non-hereditary), approximately 10% of all breast cancer and
25% of all ovarian cancers occur because an individual was born
with a harmful change in a gene that increased their risk to develop
cancer. These harmful changes are also known as pathogenic
variants and can be identified through genetic testing.
Genes and Lifetime Risks
Many genes have been associated with an increased risk of breast
and ovarian cancer. These genes can be categorized into three main
groups: High-Risk, Moderate-Risk and Newer-Risk.
Table 1 reviews the genes associated with an increased risk of
breast and/or ovarian cancer in the presence of a pathogenic
variant and provides information on other cancers and/or tumors
associated with these genes. Specific lifetime risk estimates are
provided when available and are based on published medical
literature.
GUIDE FOR HEREDITARY BREAST & OVARIAN CANCER
1
CLINICAL INFORMATION
Hereditary Breast and Ovarian Cancer
High-Risk Genes
Moderate-Risk Genes
Newer-Risk Genes
CLINICAL INFORMATION
Table 1: Lifetime Cancer and/or Tumor Risks for Genes
Associated with Hereditary Breast and Ovarian Cancer
Gene
Lifetime Cancer and/or Tumor Risks*
BRCA11,2
Female breast (57-87%), Ovarian (24-54%), Prostate,
Male breast, Pancreatic, Fallopian tube, Primary peritoneal,
Endometrial
BRCA2 1,3
Female breast (41-84%), Prostate (20-34%), Ovarian (11-27%),
Pancreatic (5-7%), Male breast (4-7%), Melanoma, Fallopian tube,
Primary peritoneal, Endometrial
CDH11
Gastric cancer (40-83%), Female breast (39-52%), Colon
EPCAM,
MLH1,
MSH2,
MSH6,
PMS2 1
Colorectal (11-80%), Endometrial (12-61%), Ovarian (1-24%),
Gastric (<1-20%), Urinary tract (1-10%), Pancreatic, Biliary tract,
Small bowel, Brain, Sebaceous tumors
PALB2 1,4
Female breast (25-58%), Male breast, Pancreatic, Ovarian
PTEN 1,5
Female breast (25-85%), Thyroid (3-38%), Endometrial (5-28%),
Colon, Renal, Melanoma, Gastrointestinal polyps
TP53
Female breast, Sarcoma-bone and soft tissue, Brain,
Hematologic malignancies, Adrenocortical carcinoma, among
others.
Overall risk for cancer: nearly 100% in females, 73% in males
1
Tumor spectrum is representative of Lynch syndrome; data are limited with regard to the
association of certain cancers with pathogenic variants in MSH6, PMS2 and EPCAM
Female breast, Colon, Pancreatic
ATM 1
BRIP1
Ovarian, Female breast
CHEK2 1,7
Female breast, Male breast, Colon, Prostate, Thyroid, Endometrial,
Ovarian
RAD51C 1,8
Ovarian, Female breast
RAD51D 1,9
Ovarian, Female breast
BARD110,11
Female breast, Ovarian
FANCC 12
Female breast
NBN 13
Female breast, Melanoma, Non-Hodgkin lymphoma
XRCC2 14
Female breast, Pancreatic
1,6
*Lifetime risks are provided when available. Risks relate to carriers of a single
pathogenic variant.
2
High-Risk Genes
High-risk genes are well-studied, and pathogenic variants in these
genes are associated with a significantly increased risk (greater
than 4-fold risk when compared with the general population) to
develop one or more cancers. These genes are often associated
with well-defined hereditary cancer syndromes, which generally
have published guidelines for screening and prevention. Patients
with pathogenic variants in these genes may develop cancer and/
or tumors at young ages or may have an increased risk for multiple
cancer diagnoses in a lifetime.
High-risk genes associated with an increased risk of breast and/
or ovarian cancer include BRCA1, BRCA2 (BRCA-Related Breast
and/or Ovarian Cancer syndrome); CDH1 (Hereditary Diffuse Gastric
Cancer syndrome); EPCAM, MLH1, MSH2, MSH6, PMS2 (Lynch
syndrome); PALB2; PTEN (PTEN Hamartoma Tumor syndrome,
including Cowden syndrome); and TP53 (Li-Fraumeni syndrome).
Figure 1 provides the lifetime breast and/or ovarian cancer risks
when a pathogenic variant is identified in these high-risk genes.
Figure 1: Lifetime Risk of Breast and Ovarian Cancer Associated with Pathogenic Variants in High-Risk Genes
Female Breast Cancer*
100
Ovarian Cancer
90 54-87%
25-85%
41-84%
80
Range of Reported Risk
increased**
Cancer Risk (%)
70
60
50
25-58%
24-54%
39-52%
40
11-27%
30
1-24%
20
12%
10
0
increased**
BRCA1
BRCA2
CDH1
EPCAM,
PALB2
MLH1, MSH2,
MSH6, PMS2
1-2%
PTEN
TP53
General
Population
High-Risk Genes
* BRCA1, BRCA2, and PALB2 pathogenic variants are also associated with an increased risk for male breast cancer.
** Lifetime risks of cancer are known to be significantly increased for individuals with a pathogenic variant, although
a precise lifetime risk is unknown.
GUIDE FOR HEREDITARY BREAST & OVARIAN CANCER
3
Moderate-Risk Genes
Moderate-risk genes are often well-studied, and pathogenic
variants in these genes are associated with a more modest risk
(approximately a 2- to 4-fold risk when compared with the general
population) to develop one or more cancers. Generally, there are
limited guidelines for screening and surveillance. Similar to highrisk genes, patients with pathogenic variants in these genes may
develop cancer at an early age and may develop multiple cancer
diagnoses in a lifetime.
Newer-Risk Genes
In addition to high-risk and moderate-risk genes, other genes have
been identified that are not as well-studied. Often the association
with cancer may be newly discovered, or there may be limited
data on the degree of cancer risk and/or full spectrum of tumors
associated with genetic variants in these genes. Guidelines for
screening and prevention are limited or not available.
4
Identifying Patients at Risk for Hereditary
Breast and Ovarian Cancer
Individuals with a personal and/or family history of the following may
be at risk for hereditary breast and ovarian cancer. Family history
includes first, second, and third-degree blood relatives (including
parents, siblings, children, aunts/uncles, cousins, and grandparents).
GUIDE FOR HEREDITARY BREAST & OVARIAN CANCER
5
TEST INFORMATION
It is important to provide detailed information on the personal and
family histories of cancer, including ages of diagnosis, pathology,
and relationship between family members. This information can
help determine if testing is appropriate and which test is medically
necessary, as well as may impact insurance coverage.
TEST INFORMATION
• Breast cancer diagnosed under 50 years of age
• Multiple cancers in one person, either of the same origin (such
as two separate breast cancers) or of different origins (such as
breast cancer and ovarian cancer)
• Ovarian cancer or male breast cancer at any age
• Multiple relatives diagnosed with the same or related cancers
(including breast, ovarian, pancreatic and/or prostate) on the
same side of the family and spanning multiple generations
• Ashkenazi Jewish ancestry with a history of breast, ovarian or
pancreatic cancer
• A known pathogenic variant in a blood relative
Test Options
TEST INFORMATION
Below are the tests available for individuals at risk for hereditary
breast and ovarian cancer.
Test Name
Genes Included
Turn Around
Time
BRCA1/BRCA2
Sequencing
and Deletion
Duplication
Analysis*
BRCA1, BRCA2
8-10 days
Breast Cancer
High/Moderate
Risk Panel
(8 genes)
ATM, BRCA1, BRCA2, CDH1, CHEK2,
PALB2, PTEN, TP53
2 weeks
Breast/Ovarian
Cancer Panel
(20 genes)
ATM, BARD1, BRCA1, BRCA2, BRIP1,
CDH1, CHEK2, EPCAM, FANCC, MLH1,
MSH2, MSH6, NBN, PALB2, PMS2,
PTEN, RAD51C, RAD51D, TP53, XRCC2
3 weeks
High/Moderate
Risk Panel
(23 genes)
APC, ATM, BMPR1A, BRCA1, BRCA2,
BRIP1, CDH1, CDKN2A, CHEK2,
EPCAM, MLH1, MSH2, MSH6,
MUTYH, PALB2, PMS2, PTEN, RAD51C,
RAD51D, SMAD4, STK11, TP53, VHL
3 weeks
Comprehensive
Cancer Panel
(32 genes)
APC, ATM, AXIN2, BARD1, BMPR1A,
BRCA1, BRCA2, BRIP1, CDH1, CDK4,
CDKN2A, CHEK2, EPCAM, FANCC,
MLH1, MSH2, MSH6, MUTYH, NBN,
PALB2, PMS2, POLD1, POLE, PTEN,
RAD51C, RAD51D, SCG5/GREM1,
SMAD4, STK11, TP53, VHL, XRCC2
3 weeks
OncoGeneDx
Custom Panel
(up to 61 genes)
ALK, APC, ATM, AXIN2, BAP1, BARD1,
BMPR1A, BRCA1, BRCA2, BRIP1,
CDC73, CDH1, CDK4, CDKN2A,
CHEK2, DICER1, EPCAM, FANCC, FH,
FLCN, MAX, MEN1, MET, MITF, MLH1,
MSH2, MSH6, MUTYH, NBN, NF1, NF2,
PALB2, PHOX2B, PMS2, POLD1, POLE,
PRKAR1A, PTCH1, PTEN, RAD51C,
RAD51D, RB1, RET, SCG5/GREM1,
SDHA, SDHAF2, SDHB, SDHC, SDHD,
SMAD4, SMARCA4, SMARCB1, STK11,
SUFU, TMEM127, TP53, TSC1, TSC2,
VHL, WT1, XRCC2
3 weeks
*Targeted testing for the three common pathogenic variants found in the Ashkenazi
Jewish population is also available
6
Additional testing options are available, including targeted variant
testing for a previously identified pathogenic or likely pathogenic
variant in a family member. Appropriate test selection depends on
the specific clinical history of a patient, including family history of
cancer and/or previous personal or familial test results. Testing for
most genes includes sequencing and deletion/duplication analysis
via next-generation sequencing and/or exon array testing.
Sample Submission
Genetic testing can be performed on blood, oral rinse or extracted
DNA samples. GeneDx test kits are available to ordering providers,
and include sample collection items (such as mouthwash for oral
rinse and collection tubes), the necessary sample submission
paperwork, and a self-addressed return shipping label.
Additionally, all test requisition forms are available for download
from the GeneDx website: www.genedx.com/forms
Please note that all testing must be performed under the guidance
of a healthcare provider. For more information on the sample
submission process, please visit our website:
www.genedx.com/supplies or email us at: [email protected]
GUIDE FOR HEREDITARY BREAST & OVARIAN CANCER
7
Genetic Testing Process
Patient Identification
Sample Submission
Discussion of personal
and family history
The patient’s sample
and necessary
paperwork are sent
to the laboratory
Explanation of genetic
testing options
Genetic Testing
At the laboratory, genetic testing for most
genes includes next-generation sequencing
and/or exon array analysis
Genetic Test Results
Final Report
BRCA1/2
Breast/Ovarian Cancer Panel Negative
PHYSI
g and Deletion/D
Sequencin
CIAN
Center
Information for Individuals Who Have Tested Negative
for Pathogenic
Variants
Dr. XYZ Oncology
NEGATIVE
Report
Analysis
Genetic Test
uplication
Oncology
Contains information on the results of
the genetic test and available medical
management options
PATIE
NT
Sample Patient Age: 28 Sex:
DOB: 02/21/1983
111111
Patient ID:
Specimen
What This Test Result Means
For You:
Additional
Healthcare
Provider:
uplication
ng and Deletion/D
SAMPL
E
ID: 111111111
Date of Report:
F
4/29/2016
4/20/2016
Date Collected: 4/22/2016
Date Received: IN EDTA
Source: BLOOD
Address:
ST
St
555 Main
123 MAIN NJ 12345
NJ
,
Anytown,
ANYTOWN
You have undergone genetic testing for genes associated with an increased M1
risk for breast and/or ovarian
Your test was negative for
90cancer.12345
X1111
any pathogenic (harmful) variants.
90 F: 123-456-78
P: 123-456-78
Test Results:
Analysis
If you have been diagnosed with cancer, the reason why you developed cancer remains
unknown. It is possible that you have a
Sequenci
cancer.
BRCA2
pathogenic variant in an untested area of the genes analyzed or youBRCA1/2
have a pathogenic variant
in an
unidentified gene. It is also possible
of breast
BRCA1,
Evaluated:
that your cancer was caused by factors other than your genes. You should
your medical management as recommended Family
by your history
Genes continue
l cancer.
doctor.
id endometria
Test Indication
endometrio
of
If you have never been diagnosed with cancer or symptoms associated with onehistory
of the genes/syndromes
on this panel, and have
undergone testing based on a family history of cancer with no known Personal
pathogenic variant in the family, this result does not provide an
Zygosity
explanation for the cancer in your family. Your risk to develop cancer may still be increased and you should continue with medical
GOUS
management based on your medical and/or family history. Your result may be negative because there is a genetic predisposition in your
HETEROZY
ion
Classificat
or BRCA2.
family that you did not inherit or it may be that the cancer in your family is caused by something
beyond the genes included in this test.
: POSITIVE
of BRCA1
Summary
To clarify which of these explanations is more likely, it may be helpful to
test a member
of your family who has been diagnosed withPATHOGENIC
Results
plication analysis
Results
cancer in order to determine if the cause of the cancer in your family can be identified. Testing
other family members
) may also help to
or deletion/du
(p.Cys61Gly
clarify your risk of developing cancer.
Gene
by sequencing
c.181T>G
For Your Family:
BRCA1
No additional
reportable
variants were
detected
Although testing was negative, your family members may still be at increased risk for developing cancer. If a genetic cause for the
cancer in you and/or your family has not been identified, genetic testing for family members who have not been diagnosed with cancer
may not be useful. In some cases, it may be helpful for other relatives with a cancer diagnosis to undergo this testing, particularly if
diagnosed at a young age or with a less common type of cancer such as ovarian cancer.
Share a copy of your test report with your biologic family members, so that their doctors knows which genes were tested.
Clinical Summary
The final report is sent to the ordering
healthcare provider
for a pathogenic
Ovarian
Breast and
women
with Hereditary breast cancer in
for
BRCA1, consistent
to 87% risk
variant in
with a 57%
associated
clinical summary.
are
If your family members would like to learn more about their risk for developing cancer, genetic
counseling us
is recommended.
The National
in BRCA1
n for detailed
is heterozygo
variants
Society of Genetic Counselors maintains a list of national and internationalThis
genetic
counselors. Visit
www.nsgc.org
to locate a genetic
individual
interpretatio
Pathogenic
cancer. See
counselor near you.
syndrome.
for ovarian
Cancer
to 54% risk
and a 24%
nt
of these results.
manageme
the implications
Ovarian include
ed to discuss
t: Breast and
in the current
variant identified
Guidelines
Breast
the pathogenic
family members.
also having for this individual’s
• The NCCN ations for Hereditary
.
chance of
counselors
recommend
is available
up to a 50%
our genetic
Glossary
or
relatives have for pathogenic variants
call one of
genetic variant
detail, please
• First degreeTargeted testing
with the same
in further
Gene: A defined segment of DNA that provides instructions for the cells of the bodyindividual.
to make a specific protein.
and families please visit
these results
to discuss
more,
Genetic: Refers to a medical condition that is caused, at least in part, by an alteration (or pathogenic
in a person’s DNA. Genetic
likevariant)
enable individuals
created to d information. To learn
conditions are often inherited, or passed down through the family tree.
• If you would
ticNIH initiative
brca2-gene
Pathogenic Variant: An alteration in DNA considered to increase the risk for or cause the development
particular
disease. de-identifie
nnectofisa an
/brca1-andand share
enedx.com
• GenomeCo
to connect
www.oncog
rg.
visit:
medical history
econnect.o
Patient Resources
results, please
www.genom
about these
• Facing Our Risk Of Cancer Empowered (FORCE): www.facingourrisk.org
more information
• Bright Pink: www.brightpink.org
• To learn itive-results
• National Cancer Institute: www.cancer.gov/cancertopics/genetics
testing-pos
• GeneDx: www.oncogenedx.com
Medical Management Options
ndations
Recomme
There are a variety of management strategies available to individuals at an increased
risk to develop breast
and/or ovarian cancer based
is recommend
Assessmen
counseling
on genetic test results and/or personal or family history risk factors. Medical management
and you should
syndrome.
milial High-Risk
• Genetic varies for each patient,
for Genetic/Fa and Ovarian Cancer
discuss your specific options with your doctor.
Page 1 of
4
Signed By:
Report Electronically
MS, CGC
Kristin Theobald,
Genetic Counselor
Signed By:
F: (301) 710-6594
FACMG
Inc.
Report Electronically
P: (888) 729-1206
MBBS, PhD,
Laboratories,
MD 20877
Ying Wang,
Geneticist
Gaithersburg,
unit of BioReference
a business
Clinical Molecular
Perry Parkway,
GeneDx is
GeneDx 207
Ph.D., FACMG
Anne Maddalena,
Director
Laboratory
ology
genedx.com/onc
© 2016 GeneDX. All rights reserved. 91459 6/2016
Information current as of 6/2016
Post-Test Discussion
Healthcare provider discusses the test
results, medical management options,
and implications for family members
with the patient
8
Genetic Test Results
Nearly all test results fall into one of four categories: positive
(pathogenic variant), likely pathogenic variant, negative and a
variant of uncertain significance (VUS). Genetic counseling is
recommended prior to and following genetic testing to understand
the benefits and limitations of testing.
Final Report
Positive Result
Oncology Genetic Test Report
BRCA1/2 Sequencing and Deletion/Duplication Analysis
PHYSICIAN
A positive result indicates a genetic
variant (change) was identified in
a specific gene that is pathogenic
(harmful). With a positive test result,
the risk to develop a particular disease
(in this case, cancer and/or tumors) is
increased. The lifetime risk for cancer
and/or tumors depends on which gene
was identified as having the pathogenic
variant.
Dr. XYZ Oncology Center
123 MAIN ST
ANYTOWN, NJ 12345
X1111 M1
P: 123-456-7890 F: 123-456-7890
PATIENT
Sample Patient
DOB: 02/21/1983 Age: 28 Sex: F
Patient ID: 111111
Address:
555 Main St
Anytown, NJ
12345
SAMPLE
Specimen ID: 111111111
Date of Report: 4/29/2016
Date Collected: 4/20/2016
Date Received: 4/22/2016
Source: BLOOD IN EDTA
Additional Healthcare Provider:
BRCA1/2 Sequencing and Deletion/Duplication Analysis
Genes Evaluated: BRCA1, BRCA2
Test Indication
Personal history of endometrioid endometrial cancer. Family history of breast cancer.
Results Summary: POSITIVE
Gene
BRCA1
Results
c.181T>G (p.Cys61Gly)
Classification
Zygosity
PATHOGENIC
HETEROZYGOUS
No additional reportable variants were detected by sequencing or deletion/duplication analysis of BRCA1 or BRCA2.
Clinical Summary
This individual is heterozygous for a pathogenic variant in BRCA1, consistent with Hereditary Breast and Ovarian
Cancer syndrome. Pathogenic variants in BRCA1 are associated with a 57% to 87% risk for breast cancer in women
and a 24% to 54% risk for ovarian cancer. See interpretation for detailed clinical summary.
Recommendations
• Genetic counseling is recommended to discuss the implications of these results.
• The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian include management
recommendations for Hereditary Breast and Ovarian Cancer syndrome.
• First degree relatives have up to a 50% chance of also having the pathogenic variant identified in the current
individual. Targeted testing for pathogenic variants is available for this individual’s family members.
• If you would like to discuss these results in further detail, please call one of our genetic counselors.
• GenomeConnect is an NIH initiative created to enable individuals and families with the same genetic variant or
medical history to connect and share de-identified information. To learn more, please visit
www.genomeconnect.org.
• To learn more information about these results, please visit: www.oncogenedx.com/brca1-and-brca2-genetictesting-positive-results
Page 1 of 4
Report Electronically Signed By:
Ying Wang, MBBS, PhD, FACMG
Clinical Molecular Geneticist
Anne Maddalena, Ph.D., FACMG
Laboratory Director
Report Electronically Signed By:
Kristin Theobald, MS, CGC
Genetic Counselor
GeneDx 207 Perry Parkway, Gaithersburg, MD 20877 P: (888) 729-1206 F: (301) 710-6594
GeneDx is a business unit of BioReference Laboratories, Inc.
genedx.com/oncology
Likely Pathogenic Variant Result
A likely pathogenic variant result indicates that there is a variant in
a specific gene for which there is significant, but not conclusive,
evidence that there is a risk to develop a particular disease (in this
case, cancer and/or tumors). The lifetime risk for cancer and/or
tumors depends on which gene was identified as having the likely
pathogenic variant. With this type of result, a medical management
plan may include similar options as described above for a positive
result, including enhanced screening, risk-reducing options and
testing of family members.
GUIDE FOR HEREDITARY BREAST & OVARIAN CANCER
9
RESULTS / MANAGEMENT
Knowledge of a positive result provides valuable information
to patients, healthcare providers, and family members as they
develop a medical management plan to direct treatment of a
current cancer diagnosis or reduce the risk for or improve early
detection of future cancers and/or tumors. A medical management
plan may include enhanced screening or in some cases, riskreducing surgery. Furthermore, testing family members may be
appropriate and can allow for more accurate predictions of their
cancer and/or tumor risks.
Negative Result
NEGATIVE
A negative result means that no reportable variants were identified.
This result can have different implications depending on the
specific circumstances related to the testing.
In many cases when no one in the family
has previously been found to have a
pathogenic variant, the reason for the
patient’s personal or family history of
cancer remains unknown. The result may
be negative because there is a genetic
predisposition in the family that the patient
did not inherit or it may be that the cancers
and/or tumors in the family are caused
by something beyond the genes included on their test. The risk
for future cancers and medical management recommendations
should be based on personal and/or family history of cancer.
Breast/Ovarian Cancer Panel Negative
Information for Individuals Who Have Tested Negative for Pathogenic Variants
Test Results:
You have undergone genetic testing for genes associated with an increased risk for breast and/or ovarian cancer. Your test was negative for
any pathogenic (harmful) variants.
What This Test Result Means
For You:
If you have been diagnosed with cancer, the reason why you developed cancer remains unknown. It is possible that you have a
pathogenic variant in an untested area of the genes analyzed or you have a pathogenic variant in an unidentified gene. It is also possible
that your cancer was caused by factors other than your genes. You should continue your medical management as recommended by your
doctor.
If you have never been diagnosed with cancer or symptoms associated with one of the genes/syndromes on this panel, and have
undergone testing based on a family history of cancer with no known pathogenic variant in the family, this result does not provide an
explanation for the cancer in your family. Your risk to develop cancer may still be increased and you should continue with medical
management based on your medical and/or family history. Your result may be negative because there is a genetic predisposition in your
family that you did not inherit or it may be that the cancer in your family is caused by something beyond the genes included in this test.
To clarify which of these explanations is more likely, it may be helpful to test a member of your family who has been diagnosed with
cancer in order to determine if the cause of the cancer in your family can be identified. Testing other family members may also help to
clarify your risk of developing cancer.
For Your Family:
Although testing was negative, your family members may still be at increased risk for developing cancer. If a genetic cause for the
cancer in you and/or your family has not been identified, genetic testing for family members who have not been diagnosed with cancer
may not be useful. In some cases, it may be helpful for other relatives with a cancer diagnosis to undergo this testing, particularly if
diagnosed at a young age or with a less common type of cancer such as ovarian cancer.
Share a copy of your test report with your biologic family members, so that their doctors knows which genes were tested.
If your family members would like to learn more about their risk for developing cancer, genetic counseling is recommended. The National
Society of Genetic Counselors maintains a list of national and international genetic counselors. Visit www.nsgc.org to locate a genetic
counselor near you.
Medical Management Options
There are a variety of management strategies available to individuals at an increased risk to develop breast and/or ovarian cancer based
on genetic test results and/or personal or family history risk factors. Medical management varies for each patient, and you should
discuss your specific options with your doctor.
Glossary
Gene: A defined segment of DNA that provides instructions for the cells of the body to make a specific protein.
Genetic: Refers to a medical condition that is caused, at least in part, by an alteration (or pathogenic variant) in a person’s DNA. Genetic
conditions are often inherited, or passed down through the family tree.
Pathogenic Variant: An alteration in DNA considered to increase the risk for or cause the development of a particular disease.
Patient Resources
• Facing Our Risk Of Cancer Empowered (FORCE): www.facingourrisk.org
• Bright Pink: www.brightpink.org
• National Cancer Institute: www.cancer.gov/cancertopics/genetics
• GeneDx: www.oncogenedx.com
RESULTS / MANAGEMENT
© 2016 GeneDX. All rights reserved. 91459 6/2016
Information current as of 6/2016
When an individual tests negative for a familial pathogenic variant
that has already been identified in another family member, this is
considered a true negative test result. In most cases, the risk for
cancer is not expected to be greater than the general population.
Sometimes this interpretation may be limited if the family
member’s pathogenic variant was identified in a gene described as
moderate-risk or newer-risk.
Depending upon the patient’s personal and family history of
cancer, additional genetic testing may be indicated for the patient
or a family member. Sometimes there are other genes that can
explain the family history of cancer, or areas of a gene which were
not examined with the initial test. A genetic specialist or other
healthcare provider can determine if further genetic testing is
appropriate.
Variant of Uncertain Significance (VUS) Result
A variant of uncertain significance (VUS) result means that a
change in a specific gene was identified, however the effect of the
variant cannot be clearly established. There may be conflicting or
incomplete information in the medical literature about this variant
10
and its association with an increased risk of cancers and/or tumors
is unknown. In other words, it cannot be determined yet whether
this variant is associated with an increased risk of cancer and/
or tumors or it is a harmless (normal) variant. In some cases, it
may be helpful to test other family members through our Variant
Testing Program to help clarify the risk. Over time, the VUS may
become reclassified to either a “positive” or “negative” test result.
The patient’s risk for future cancers and medical management
recommendations should typically be based on personal and/or
family history until the VUS is reclassified.
Test Reports
Test reports contain detailed information about a specific genetic
result and, if available, medical management options. Additional
support is available from our laboratory genetic counselors and
local genetic providers within your area. Genetic counseling
services across the country can be found at: www.nsgc.org
Test results are available within three weeks after a sample is
received in the laboratory. Once complete, test results are sent to
the ordering healthcare provider. The healthcare provider should
share those results and discuss them in the context of the reported
personal and family histories.
Medical Management Based on Genetic
Test Results
Medical management options for early detection or risk reduction
are available for many individuals found to have a pathogenic
variant in a gene associated with hereditary cancer. The options
may include enhanced screening, risk reducing surgery, and in
some cases, risk reducing medication. Options for screening
and risk reduction are based on national guidelines or consensus
statements, when available, and are specific to the gene in which
a pathogenic variant is identified.
Information on screening and risk reduction options are included
in the report for a positive and likely pathogenic test result. A
summary of medical management options are provided in Table 2.
GUIDE FOR HEREDITARY BREAST & OVARIAN CANCER
11
Table 2: Medical Management Options for Genes Associated with
Hereditary Breast and Ovarian Cancer
RESULTS / MANAGEMENT
Gene
Medical Management Guidelines
ATM1
•
•
•
•
Increased breast awareness, including breast self-examination
Clinical breast examination
Breast MRI and mammogram starting at an early age
Consider breast cancer risk-reduction strategies
BRCA1,
BRCA21
• Increased breast awareness, including breast self-examination for both men and
women
• Clinical breast examination for both men and women
• Breast MRI and mammography starting at an early age
• Consider prophylactic mastectomy
• Bilateral salpingo-oophorectomy (BSO)
• Consider transvaginal ultrasound of ovaries and CA-125 blood tests for women
who have not had a BSO
• Consider the use of risk-reducing medications (such as tamoxifen, raloxifene and
oral contraceptives)
• Consider prostate cancer screening starting at an early age
• Consider pancreatic cancer screening and full body skin examination dependent
on family history
BRIP11
• Consider bilateral salpingo-oophorectomy
CDH11,15
•
•
•
•
•
•
•
•
Increased breast awareness, including breast self-examination
Clinical breast examination
Breast MRI and mammography starting at an early age
Consider prophylactic mastectomy
Consider the use of risk-reducing medications (such as tamoxifen or raloxifene)
Prophylactic gastrectomy
In the absence of gastrectomy, upper endoscopy
Consider colonoscopy beginning at an early age dependent on family history
CHEK21,16
•
•
•
•
•
Increased breast awareness, including breast self-examination
Clinical breast examination
Breast MRI and mammogram starting at an early age
Consider breast cancer risk-reduction strategies
Periodic colonoscopy starting at an early age*
For all genes
EPCAM
MLH1
MSH2
MSH6
PMS216
• Frequent colonoscopy (every 1-2 years in many cases) starting at an early age
• Consider the option of prophylactic colectomy, particularly if the patient requires
surgery to address a colonic neoplasm or is not an optimal candidate for
surveillance
• Consider endometrial/ovarian cancer screening, which may include endometrial
biopsy, transvaginal ultrasound and CA-125 blood tests
• Consider prophylactic hysterectomy and salpingo-oophorectomy once a woman
has completed childbearing
For EPCAM, MLH1, MSH2 only
• Consider upper endoscopy with extended duodenoscopy
• Consider urinalysis to screen for urinary tract cancers
• Consider physical examination with neurological examination
12
Gene
PALB21,17
Medical Management Guidelines
•
•
•
•
Increased breast awareness, including breast self-examination
Clinical breast examination
Breast MRI and mammogram starting at an early age
Consider risk-reduction strategies, including the option of prophylactic
mastectomy
• Consider pancreatic cancer screening dependent on family history
•
•
•
•
PTEN1
•
•
•
•
•
•
•
Increased breast awareness, including breast self-examination
Clinical breast examination
Breast MRI and mammography starting at an early age
Consider endometrial biopsy and/or transvaginal ultrasound starting at an early
age; encourage patient education and prompt response to symptoms
Options of prophylactic mastectomy and hysterectomy can be discussed
Periodic colonoscopy starting at an early age
Thyroid ultrasound
Consider renal ultrasounds
Physical examination
Consider dermatological examination
One or more management recommendations may begin in childhood or
adolescence
RAD51C1 • Consider bilateral salpingo-oophorectomy
RAD51D1 • Consider bilateral salpingo-oophorectomy
Increased breast awareness, including breast self-examination
Clinical breast examination
Breast MRI and mammography starting at an early age
Consider prophylactic mastectomy
Consider increased colonoscopy screening starting at an early age
Consider whole body MRI, including brain imaging
Comprehensive physical examination, including neurologic and skin examination
starting at an early age
• Use caution regarding radiation therapy for cancer
• Additional surveillance based on family history of cancer
• One or more management recommendations may begin in childhood or
adolescence
* Given limited data to support these guidelines, caution should be used when making
recommendations.
For the details on the specific medical management options, including
frequency of screening and ages to begin surveillance, please review the
referenced guidelines or consensus statements.
GUIDE FOR HEREDITARY BREAST & OVARIAN CANCER
13
RESULTS / MANAGEMENT
TP531
•
•
•
•
•
•
•
Implications for Family Members
Regardless of the result, patients should share their test report
with their blood relatives, who can then discuss the results with
their healthcare providers. Sharing a copy of the test result with
family members and healthcare providers will help to determine if
additional testing is necessary and will ensure that the proper test
is ordered for relatives, if indicated.
For most positive or likely pathogenic test results, first-degree
relatives (including parents, siblings, and children) have a 50%
chance to have the same variant. The risk for other family
members to carry the variant depends on how closely related they
are to the person with a positive or likely pathogenic test result.
It is important to remember that for most of these genes, not all
people who inherit a pathogenic or likely pathogenic variant will
develop cancer and/or tumors, but the chance is increased above
that of the general population.
In some cases, certain genes may also be associated with an
autosomal recessive condition. This occurs when an individual
inherits two pathogenic variants, one from each parent. For most
autosomal recessive conditions, the two pathogenic variants occur
within the same gene and affect both copies of that gene. The
genes associated with autosomal recessive conditions include
ATM, BRCA2, BRIP1, FANCC, NBN, PALB2, RAD51C, XRCC2
and the Lynch syndrome genes (EPCAM, MLH1, MSH2, MSH6
and PMS2).18-22 When an individual has two variants in these
genes, the cancer and/or tumor risks and the risks to family
members are different than described above. In the case of a
positive result, the report will provide additional information on the
gene, inheritance and cancer and/or tumor risks.
14
Genetic Counseling
Prior to genetic testing, patients should speak to their healthcare
provider and/or a genetic specialist about their personal and
family history of cancer, allowing for cancer risk assessment.
Healthcare providers should discuss the benefits and limitations
of testing, as well as possible test results. These conversations
help to determine if the patient meets clinical criteria for testing,
facilitates appropriate test ordering and ensures that the patient
has provided informed consent for genetic testing.
If a pathogenic variant has already been identified in a family
member, testing of the specific variant is appropriate. If a
pathogenic variant has never been identified, an affected family
member with the highest likelihood for a positive result (such as
having early-onset disease, bilateral disease or multiple primaries)
is ideally the best person for initial testing within a family. If an
affected family member is not available, testing of an unaffected
family member can be considered, although a negative test result
will not guarantee that the individual does not have an increased
risk for cancer and/or tumors.
Once a patient makes the decision to undergo testing, posttest genetic counseling is recommended to understand the
implications of the results, including discussion of cancer risks and
appropriate medical management based on both the test results
and the patient’s medical and family histories. Genetic counseling
services across the country can be found at: www.nsgc.org
KEY INFORMATION
GUIDE FOR HEREDITARY BREAST & OVARIAN CANCER
15
Insurance Coverage and Cost for Genetic
Testing
GeneDx accepts all commercial plans and is a Medicare provider.
Additionally, GeneDx is a registered provider with several Medicaid
plans. If a patient does not have health insurance or cannot afford
to pay the cost of testing, GeneDx provides a financial assistance
program to help ensure that all patients have access to medically
necessary genetic testing.
For more information on the paperwork that is required by some
insurance carriers, as well as additional details on patient billing or
our financial assistance program, please visit our website:
www.genedx.com/billing
Genetic Information Nondiscrimation Act
The Genetic Information Nondiscrimination Act of 2008, also
referred to as GINA, is a federal law that protects Americans from
discrimination by health insurance companies and employers
based on their genetic information. However, this law does
not cover life insurance, disability insurance, or long-term care
insurance. GINA’s employment protections do not extend to
individuals in the U.S. military, federal employees, Veterans
Health Administration and Indian Health Service. Some of these
organizations may have internal policies to address genetic
discrimination. For more information, please visit:
http://genome.gov/10002328
KEY INFORMATION
Resources for Patients
Bright Pink: www.brightpink.org
Colon Cancer Alliance for Research and Education for
Lynch Syndrome (CCARE): www.fightlynch.org
Facing Our Risk of Cancer Empowered (FORCE):
www.facingourrisk.org
GeneDx: www.oncogenedx.com
National Cancer Institute: www.cancer.gov
National Society of Genetic Counselors: www.nsgc.org
16
References
1. NCCN Guidelines. Genetic/Familial High-Risk Assessment: Breast and Ovarian. (URL: http://www.nccn.org/
professionals/physician_gls/f_guidelines.asp) [February 2016 accessed]
2. Ford D et al. Risks of cancer in BRCA1-mutation carriers. The Breast Cancer Linkage Consortium. Lancet.
1994 Mar;343(8899):692-5
3. Ford D et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer
families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998 Mar;62(3):676-89
4. Ding YC et al. Mutations in BRCA2 and PALB2 in male breast cancer cases from the United States. Breast
Cancer Res Treat. 2011 Apr;126(3):771-8
5. Tan et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012 Jan
15;18(2):400-7
6. Seal S et al. Truncating mutations in the Fanconi anemia J gene BRCA1 are low-penetrance breast cancer
susceptibility alleles. Nat Genet. 2006 Nov;38(11):1239-41
7. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified
by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7
8. Meindl A et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human
cancer susceptibility gene. Nat Genet. 2010 May;42(5):410-4
9. Osher DJ et al. Mutation analysis of RAD51D in non-BRCA1/2 ovarian and breast cancer families. Br J Cancer.
2012 Apr 10;106(8):1460-3
10. Ratajska M et al. Cancer predisposing BARD1 mutations in breast-ovarian cancer families. Breast Cancer Res
Treat. 2012 Jan;131(1):89-97
11. Pennington KP et al. Germline and somatic mutations in homologous recombination genes predict platinum
response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 2014 Feb
1;20(3):764-75
12. Thompson ER et al. Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and
BLM as potential breast cancer susceptibility alleles. PLoS Genet. 2012 Sep;8(9):e1002894. doi: 10.1371/
journal.pgen.1002894. Epub 2012 Sep 27
13. Steffen J et al. Germline mutations 657del5 of the NBS1 gene contribute significantly to the incidence of
breast cancer in Central Poland. Int J Cancer. 2006 Jul 15;119(2):472-5
14. Park DJ et al. Rare mutations in XRCC2 increase the risk of breast cancer. Am J Hum Genet. 2012 Apr
6;90(4):734-9
15. NCCN Guidelines. Gastric Cancer. (URL:https://www.nccn.org/professionals/physician_gls/pdf/ gastric.pdf)
[March 2016 accessed]
16. NCCN Guidelines. Genetic/Familial High-Risk Assessment: Colorectal. (URL: http://www.nccn.org/professionals/
physician_gls/f_guidelines.asp) [June 2016 assessed]
17. Canto MI et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management
of patients with increased risk for familial pancreatic cancer. Gut. 2013 Mar;62(3):339-47
18. Gatti R. Ataxia-Telangiectasia. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird
TD, Fong CT, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of
Washington, Seattle; 1993-2016. 1999 Mar 19 [updated 2010 Mar 11]
19. Alter BP and Kupfer G. Fanconi Anemia. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean
LJH, Bird TD, Fong CT, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA):
University of Washington, Seattle; 1993-2016. 2002 Feb 14 [updated 2013 Feb 3]
20. Varon R, DemuthI and Digweed M. Nijmegen Breakage Syndrome. In: Pagon RA, Adam MP, Ardinger
HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Fong CT, Mefford HC, Smith RJH, Stephens K, editors.
GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. 1999 May 17 [updated
2014 May 8]
21. Shamseldin HE et al. Exome sequencing reveals a novel Fanconi group defined by XRCC2 mutation. J Med
Genet. 2012 Mar;49(3):184-6
22. Wimmer et al. Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the
European consortium ‘care for CMMRD’ (C4CMMRD). J Med Genet. 2014 Jun;51(6):355-65
Select references provided. For additional details, please visit
www.genedx.com/oncology-genetics
GUIDE FOR HEREDITARY BREAST & OVARIAN CANCER
17
About GeneDx
GeneDx was founded in 2000 by two scientists from the National Institutes
of Health (NIH) to address the needs of patients diagnosed with rare
disorders and the clinicians treating these conditions. Today, GeneDx has
grown into a global industry leader in genomics, having provided testing to
patients and their families in over 55 countries. Led by its world-renowned
whole exome sequencing program, and an unparalleled comprehensive
genetic testing menu, GeneDx has a continued expertise in rare and
ultra-rare disorders. Additionally, GeneDx also offers a number of other
genetic testing services, including: diagnostic testing for hereditary cancers,
cardiac, mitochondrial, and neurological disorders, prenatal diagnostics,
and targeted variant testing. At GeneDx, our technical services are backed
by our unmatched scientific expertise and our superior customer support.
Our growing staff includes more than 30 geneticists and 100 genetic
counselors specializing in clinical genetics, molecular genetics, metabolic
genetics, and cytogenetics who are just a phone call or email away to
assist you with your questions and testing needs. We invite you to visit our
website: www.genedx.com to learn more about us.
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Information current as of 08/16