Please answer
26yo woman has several first degree relatives who have died of breast cancer in their 40s. She has heard of the BRCA1 gene and is considering the possibility of a genetic link in her family. She chooses to have BRCA1 testing and her results are positive. This is an autosomal dominant trait but unlike other genetic diseases, like Huntington’s, for example, it is not 100% penetrant. Rather, this is associated with a 45-85% lifetime risk of breast cancer compared to the 12% risk for any woman. There may be as many as 700 variants of BRCA1. At this time, it is unknown where each of those variants fall in the risk range.
1. Does this woman have a moral obligation to notify her future spouse of her test results? Why or why not?
2. If you were seeing this woman as an APRN, how would you counsel her on what she should or should not share with her future spouse? Why?
3. If this woman instead had a genetic disorder that was 100% penetrant, would it change your position on 1 and/or 2? Why?
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A new pathogenic mutation of the BRCA1 gene in
a patient with ovarian cancer
A case report
Niu Yizhen, MDa,b, Li Kemin, MDa,b, Li Qingli, PhDa,b, Wang Danqing, PhDa,b,
Yin Rutie, PhDa,b,
, Song Liang, PhDa,b
Abstract
Rationale: The breast cancer susceptibility gene (BRCA) is an important tumor suppressor gene and tumor susceptibility gene.
Germ line BRCA1/2 mutations significantly increase the risk of breast cancer and other cancers in women.
Patient concerns: A 48-year-old woman was diagnosed with breast cancer at the age of 42 and subsequently diagnosed with
ovarian cancer at the age of 48. Her sister had a history of breast cancer and her mother died from ovarian cancer.
Diagnoses: The patient has a family history of tumors. BRCA1/2 mutations was proved in this family members.
Interventions: Sanger sequencing was used to evaluate the BRCA1/2 gene status of the patient and her sister to identify the
genetic mutation sites.
Outcomes: They had the same genetic mutation, namely, the c.3487_3488insA (p.Thr1163AsnfsX2) mutation in the BRCA1 gene,
which is a novel mutation.
Lessons: This novel mutation may be a new pathogenic mutation of the BRCA1 gene. Its relationship to breast and ovarian cancers
needs to be further verified in more patient cases. Moreover, mutant protein functions in both cell and animal models are also needed.
Abbreviations: BRCA = breast cancer susceptibility gene, CT = computed tomography.
Keywords: BRCA, mutation, ovarian cancer, pathogenic
1. Introduction
Ovarian cancer is one of the common malignant tumors of the
female reproductive system, with an incidence rate that ranks it as
the third most common gynecologic cancer behind cervical and
uterine cancers. However, ovarian cancer is the gynecologic
malignancy with the highest mortality rate. Clarifying the methods
of timely detection, diagnosis, and prevention of ovarian cancer to
decrease its incidence and mortality rate has been the key goal of
gynecologic oncologists for decades. With the development of
precision medicine, mutations in the breast cancer susceptibility
genes (BRCAs) including BRCA1 and BRCA2, have come to be
known to be related to the pathogenesis of hereditary ovarian and
breast cancer. Approximately 30% of hereditary ovarian and/or
breast cancer occurrences are associated with BRCA1/2 gene
mutations.[1,2] To date, there are thousands of mutation positions
that have been discovered in the BRCA1/2 genes. In the general
population, the risk of breast cancer is about 10%, and for ovarian
cancer it is about 1%, whereas the risk of breast or ovarian cancer
in women with BRCA missense mutations exceeds 80%.[1,2]
Therefore, it is necessary to conduct early screening and clinical
interventions in these high-risk populations. Herein, we report the
case of a woman diagnosed with ovarian and breast cancer, with a
mutation in the BRCA1 gene that may be a new pathogenic
mutation.
2. Case report
A 48-year-old woman, gravida 3, para 1, had been postmeno-
pausal for 2 years. At the age of 42 she underwent a left breast
radical mastectomy due to breast cancer on the left side, without
postoperative adjuvant therapy. She maintained regular outpa-
tient follow-ups. In 2016, she presented and was admitted to our
hospital due to complaints of bloating for more than 1 month
and progressive worsening. Transvaginal color Doppler ultra-
sound detected a 16.111.415.6cm mixed cystic and solid
pelvic mass with an irregular shape and a blood flow signal
resistive index=0.64 (Fig. 1A). An abdomen and pelvis
computed tomography (CT) scan revealed irregularly shaped
Editor: N/A.
Ethics approval and consent to participate: The study has been approved by the
West China Second Hospital of Sichuan University Ethics Committee.
Consent for publication: We obtained the patients informed consent orally with
respect to the publication of this case.
Funding/support: Lateral research: ovarian cancer individualized treatment
(16H0797).
The authors have no conflicts of interest to discloce.
a Department of Gynecology and Obstetrics, b Key Laboratory of Obstetrics and
Gynaecologic and Paediatric Diseases and Birth Defects of Ministry of Education,
West China Second University Hospital, Sichuan University, Chengdu, Sichuan,
PR China.
Correspondence: Yin Rutie, Department of Gynecology and Obstetrics, West
China Second University Hospital, Sichuan University, Chengdu, Sichuan, PR
China (e-mail: [emailprotected]).
Copyright 2018 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the terms of the Creative
Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-
ND), where it is permissible to download and share the work provided it is
properly cited. The work cannot be changed in any way or used commercially
without permission from the journal.
Medicine (2018) 97:38(e12371)
Received: 25 April 2018 / Accepted: 21 August 2018
http://dx.doi.org/10.1097/MD.0000000000012371
Clinical Case Report Medicine
OPEN
1
cystic and solid masses in the bilateral ovaries and fallopian tubes
the left mass measured approximately 8.15.215.6cm and
was predominantly solid. The right mass measured approxi-
mately 10.38.29.8cm and was predominantly cystic
(Fig. 1B). Enhanced CT scanning demonstrated uneven enhance-
ment, with an ovarian vascular pedicle on each side (Fig. 1C).
The serum cancer antigen 125 level was 3952.6U/mL. The
patient underwent 3 separate paracentesis procedures, with a
Figure 1. (A) Preoperative transvaginal ultrasound (the lesions were marked by red arrow heads), (B) preoperative CT (the lesions were marked by red arrow
heads), and (C) preoperative enhanced CT (the lesions were marked by red arrow heads). CT=computed tomography.
Yizhen et al. Medicine (2018) 97:38 Medicine
2
total of 6200mL of light yellow ascites removed. The ascitic fluid
was positive for tumor cells. At that time, a malignant tumor was
suspected, possibly originating from the reproductive system. On
the recto-vaginal and abdominal examinations, huge cystic-solid
masses in the pelvis and abdomen, suspected severe intestinal
adhesions, and extensive hard nodular lesions on the sacroiliac
ligaments were detected. Three gynecologic oncology specialists
and imaging specialists evaluated the CT scan images and the
findings scored 10(10/23) according to the Bristow standard,
which indicated that the predictive index score 4 would be
helpful to more accurately identify patients with advanced
epithelial ovarian carcinoma that were unlikely to undergo
optimal primary cytoreductive surgery.[3] They suggested that
such patients would not achieve satisfactory results from tumor
reduction surgery, and instead, preoperative adjuvant chemo-
therapy should be recommended. For our patient, a preoperative
paclitaxelcisplatin combined regimen (paclitaxel 175mg/m2
intravenous guttae (ivgtt)+cisplatin 75mg/m2 ivgtt, at intervals
of 3 weeks) was administered for a total of 3 courses. In late 2016,
she underwent a laparoscopic hysterectomy, bilateral salpingo-
oophorectomy, omentectomy, and pelvic and para-aortic lymph
node dissection. The surgical outcome was satisfactory with no
residual cancer foci. The postoperative biopsy results demon-
strated high-grade serous adenocarcinoma of the bilateral ovaries
that also involved the bilateral fallopian tubes and bilateral pelvic
walls, but there was no lymph node involvement (Fig. 2).
Subsequently, the patient received a postoperative paclitaxel
cisplatin regimen that included carboplatin (paclitaxel 175mg/m2
ivgtt+cisplatin 75mg/m2 ivgtt/carboplatin 400mg/m2 ivgtt, at
intervals of 3 weeks) for 8 courses. The chemotherapy was
completed in mid-2017 and the patient has continued close
follow-up to this point.
During chemotherapy she suffered from severe vomiting,
fatigue, and moderate bone marrow suppression. Her symptoms
were significantly relieved after symptomatic support treatment.
Her serum cancer antigen 125 decreased significantly to 10U/mL
after 3 cycles of preoperative chemotherapy, and it declined
progressively during the postoperative chemotherapy finally
reaching 5.1U/mL at the end of the chemotherapy course.
Follow-up lung and pelvic CT scans were performed after 3 and 8
courses of postoperative chemotherapy, respectively. Both results
showed that the patient was in a state of complete remission (CR).
After 3 courses of postoperative chemotherapy, our patients
blood was subjected to BRCA testing (Sanger sequencing,
Shenzhen BGI Clinical Laboratory Center). The results demon-
strated a frame shift mutation of the BRCA1 gene
c.3487_3488insA (p.Thr1163AsnfsX2). This patient had a
family history of malignancy, as her sister was diagnosed with
breast cancer at the age of 41 (Fig. 3). Further Sanger sequencing
confirmed that the sister had the same BRCA1 gene mutation as
our patient. In mid-2016, the sister underwent laparoscopic
hysterectomy with bilateral salpingo-oophorectomy at our
hospital. No malignant tumors were found on biopsy. She was
discharged 2 days later and had all normal follow-up evaluations.
Their mother was diagnosed with ovarian cancer at the age of 57,
which was her ultimate cause of death, and their father has gastric
cancer (Fig. 3).
3. Discussion
BRCAs are important tumor suppressor genes and tumor
susceptibility genes, comprising BRCA1 and BRCA2, which play
important roles in the homologous recombination mechanism in
DNA repair. Germ line BRCA1/2 mutations significantly increase
the risk of breast, ovarian, and other cancers in women. According
to the classification systems from the National Cancer Institute
(NCI),[4] the American College of Medical Genetics and Genomics
(ACMG),[5] and the Evidence-based Network Interpretation of
Germline Mutant Alleles (ENIGMA),[6] the BRCA genemutations
are divided into the following 5 grades, listed here with risks from
highest to lowest: pathogenic (grade 5, pathogenic probability>
0.99), possible pathogenic (grade 4, pathogenic probability 0.95
0.99), meaning unknown (grade 3, pathogenic probability 0.05
0.949), possible benign (grade 2, pathogenic probability 0.001
0.049), and benign (grade 1, pathogenic probability <0.001).
Considering that 2 members of that family (the patient with breast
cancer and ovarian cancer, and her sister with breast cancer) had
the genetic mutation at the same site, this novel frame shift
mutation in the BRCA1 gene may be a grade 5 pathogenic
mutation. Thus, women with genetic mutations at this site
are extremely likely to have the highest risk of breast and
ovarian cancers.
Figure 2. Ovarian high-grade serous adenocarcinoma (HE 100).
Figure 3. Family tree of the patient. BC=breast cancer, GC=gastric cancer,
OC=ovarian cancer.
Yizhen et al. Medicine (2018) 97:38 www.md-journal.com
3
BRCA mutation classification is based on the published data in
Europe and the United States. In 2017, for the first time and based
on a large sample, Wu et al reported that the BRCA mutation rate
in patients with ovarian cancer in China was 27.8%, of which
20.8% were BRCA1 mutations and 7.6% were BRCA2
mutations.[7] However, China has not yet established a large
database of gene mutations. Whether the mutation sites are
different from those in the European and American populations
needs to be determined from clinical and basic research combined
with patient and family histories. Continuing discoveries and
studies of new pathogenic gene mutation sites and types could
provide important guidance for screening, early diagnosis,
intervention, and treatment of ovarian cancer in China. In this
report, BRCA gene tests found a BRCA1 gene frame shift
mutation c.3487_3488insA (p.Thr 1163AsnfsX2) that resulted
in an encoding length of 1163 amino acids, which represented a
truncated polypeptide chain since the normal BRCA1 gene
encodes 1863 amino acids. Until now, there has been no report
on the functional studies and clinical significance of this
mutation, and its frequency is 0 in the One Thousand Genomes
Project. This mutation is suspected to be pathogenic. Moreover,
our ovarian cancer patient had a history of breast cancer and a
significant family history of malignant tumors. Therefore,
clinically it is recommended to escalate the frame shift mutation
of the BRCA1 gene c.3487_3488insA (p. Thr1163AsnfsX2) to a
pathogenic grade. This is a newly discovered pathogenic
mutation in the Chinese population and imparts great value to
the screening and early diagnosis of ovarian/breast cancer.
However, the new mutation has been identified only in 2 cases in
this family, because the patients mother died of ovarian cancer
many years ago, and therefore, testing of the mother could not be
performed. In addition, the protein function associated with this
mutation has yet to be completed.
4. Conclusion
The c.3487_3488insA (p.Thr1163AsnfsX2) BRCA1 mutation
may be a new pathogenic mutation in the BRCA1 gene. Its
association with breast and ovarian cancers needs to be further
verified through more case studies. Moreover, mutant protein
function research in both human cells and animal models are
also needed.
Author contributions
Design: Kemin Li, Rutie Yin; Collection: Yizhen Niu, Rutie Yin,
Qingli Li; Analysis: Kemin Li, Danqing Wang, Liang Song;
Writing: Yizhen Niu.
Data curation & resourcces: Qingli Li.
Formal analysis: Danqing Wang, Liang Song.
Methodology & Supervision: Kemin Li.
Writing original draft: Yizhen Niu.
Writing review & editing: Rutie Yin.
Rutie Yin orcid: 0000-0002-9221-6727
References
[1] Berek JS, Crum C, Friedlander M. Cancer of the ovary, fallopian tube,
and peritoneum. Int J Gynaecol Obstet 2012;119(Suppl 2):S118.
[2] Paluch-Shimon S, Cardoso F, Sessa C, et al. Prevention and screening in
BRCA mutation carriers and other breast/ovarian hereditary cancer
syndromes: ESMO Clinical Practice Guidelines for cancer prevention and
screening. Ann Oncol 2016;27:v103.
[3] Bristow RE, Duska LR, Lambrou NC, et al. A model for predicting
surgical outcome in patients with advanced ovarian carcinoma using
computed tomography. Cancer 2015;89:153240.
[4] Plon SE, Eccles DM, Easton D, et al. Sequence variant classification and
reporting: recommendations for improving the interpretation of cancer
susceptibility genetic test results. Hum Mutat 2008;29:128291.
[5] Richards S, Aziz N, Bale S, et al. Standards and guidelines for the
interpretation of sequence variants: a joint consensus recommendation of
the American College of Medical Genetics and Genomics and the
Association for Molecular Pathology. Genet Med 2015;17:40524.
[6] Consortium E. ENIGMA BRCA1/2 Gene variant Classification Criteria
(Version2.5,2017). Available from: https://enigmaconsortium.org/wp-
content/uploads/2017/12/ENIGMA_Rules_2017-06-29.pdf. (Accessed
29 Jun 2017).
[7] Wu X, Wu L, Kong B, et al. The first nationwide multicenter prevalence
study of germline BRCA1 and BRCA2 mutations in Chinese ovarian
cancer patients. Int J Gynecol Cancer 2017;27:16507.
Yizhen et al. Medicine (2018) 97:38 Medicine
4 Risk Assessment, Genetic Counseling, and Genetic Testing for
BRCA-Related Cancer
US Preventive Services Task Force
Recommendation Statement
US Preventive Services Task Force
IMPORTANCE Potentially harmful mutations of the breast cancer susceptibility 1 and 2 genes
(BRCA1/2) are associated with increased risk for breast, ovarian, fallopian tube, and peritoneal
cancer. For women in the United States, breast cancer is the most common cancer after
nonmelanoma skin cancer and the second leading cause of cancer death. In the general
population, BRCA1/2 mutations occur in an estimated 1 in 300 to 500 women and account for
5% to 10% of breast cancer cases and 15% of ovarian cancer cases.
OBJECTIVE To update the 2013 US Preventive Services Task Force (USPSTF) recommendation
on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer.
EVIDENCE REVIEW The USPSTF reviewed the evidence on risk assessment, genetic
counseling, and genetic testing for potentially harmful BRCA1/2 mutations in asymptomatic
women who have never been diagnosed with BRCA-related cancer, as well as those with
a previous diagnosis of breast, ovarian, tubal, or peritoneal cancer who have completed
treatment and are considered cancer free. In addition, the USPSTF reviewed interventions
to reduce the risk for breast, ovarian, tubal, or peritoneal cancer in women with potentially
harmful BRCA1/2 mutations, including intensive cancer screening, medications, and
risk-reducing surgery.
FINDINGS For women whose family or personal history is associated with an increased risk for
harmful mutations in the BRCA1/2 genes, or who have an ancestry associated with BRCA1/2
gene mutations, there is adequate evidence that the benefits of risk assessment, genetic
counseling, genetic testing, and interventions are moderate. For women whose personal or
family history or ancestry is not associated with an increased risk for harmful mutations in the
BRCA1/2 genes, there is adequate evidence that the benefits of risk assessment, genetic
counseling, genetic testing, and interventions are small to none. Regardless of family or
personal history, the USPSTF found adequate evidence that the overall harms of risk
assessment, genetic counseling, genetic testing, and interventions are small to moderate.
CONCLUSIONS AND RECOMMENDATION The USPSTF recommends that primary care
clinicians assess women with a personal or family history of breast, ovarian, tubal, or
peritoneal cancer or who have an ancestry associated with BRCA1/2 gene mutations with an
appropriate brief familial risk assessment tool. Women with a positive result on the risk
assessment tool should receive genetic counseling and, if indicated after counseling, genetic
testing. (B recommendation) The USPSTF recommends against routine risk assessment,
genetic counseling, or genetic testing for women whose personal or family history or ancestry
is not associated with potentially harmful BRCA1/2 gene mutations. (D recommendation)
JAMA. 2019;322(7):652-665. doi:10.1001/jama.2019.10987
Last corrected on November 12, 2019.
Editorial page 619
Author Audio Interview
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JAMA Patient Page page 702
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Corresponding Author: Douglas K.
Owens, MD, MS, Stanford University,
616 Serra St, Encina Hall, Room C336,
Stanford, CA 94305-6019
([emailprotected]).
Clinical Review & Education
JAMA | US Preventive Services Task Force | RECOMMENDATION STATEMENT
652 (Reprinted) jama.com
2019 American Medical Association. All rights reserved.
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T he US Preventive Services Task Force (USPSTF) makes rec-ommendations about the effectiveness of specific preven-tive care services for patients without obvious related signs
or symptoms.
It bases its recommendations on the evidence of both the
benefits and harms of the service and an assessment of the bal-
ance. The USPSTF does not consider the costs of providing a ser-
vice in this assessment.
The USPSTF recognizes that clinical decisions involve more con-
siderations than evidence alone. Clinicians should understand the
evidence but individualize decision-making to the specific patient
or situation. Similarly, the USPSTF notes that policy and coverage
decisions involve considerations in addition to the evidence of clini-
cal benefits and harms.
Summary of Recommendations and Evidence
The USPSTF recommends that primary care clinicians assess women
with a personal or family history of breast, ovarian, tubal, or perito-
neal cancer or who have an ancestry associated with breast cancer sus-
ceptibility 1 and 2 (BRCA1/2) gene mutations with an appropriate brief
familial risk assessment tool. Women with a positive result on the risk
assessment tool should receive genetic counseling and, if indicated af-
ter counseling, genetic testing (B recommendation) (Figure 1).
The USPSTF recommends against routine risk assessment, ge-
netic counseling, or genetic testing for women whose personal or
family history or ancestry is not associated with potentially harmful
BRCA1/2 gene mutations. (D recommendation)
Rationale
Importance
Potentially harmful mutations of the BRCA1/2 genes are associated
with increased risk for breast, ovarian, fallopian tube, and peritoneal
cancer.1-6 For women in the United States, breast cancer is the most
common cancer after nonmelanoma skin cancer and the second lead-
ing cause of cancer death.7 In the general population, BRCA1/2 mu-
tations occur in an estimated 1 in 300 to 500 women and account for
5% to 10% of breast cancer cases and 15% of ovarian cancer cases.8-11
A womans risk for breast cancer increases if she has clinically signifi-
cant mutations in the BRCA1/2 genes.12,13 Mutations in the BRCA1/2
genes increase breast cancer risk to 45% to 65% by age 70 years. Risk
of ovarian, fallopian tube, or peritoneal cancer increases to 39% for
BRCA1 mutations and 10% to 17% for BRCA2 mutations.12,13
Detection
Genetic risk assessment and BRCA1/2 mutation testing is a multi-
step process that begins with identifying patients with family or per-
sonal histories of breast, ovarian, tubal, or peritoneal cancer; family
members with known harmful BRCA1/2 mutations; or ancestry as-
sociated with harmful BRCA1/2 mutations. Risk for clinically signifi-
cant BRCA1/2 mutations can be further evaluated with genetic coun-
seling by suitably trained health care clinicians, followed by genetic
testing of selected high-risk individuals and posttest counseling about
results. The USPSTF found adequate evidence that familial risk as-
sessment tools are accurate in identifying women with increased like-
lihood of BRCA1/2 mutations. These tools can be used by primary
care clinicians to guide referrals to genetic counseling.
The USPSTF has previously established that there is adequate
evidence that current genetic tests can accurately detect known
BRCA1/2 mutations.14
Benefits of Screening, Genetic Counseling,
and Genetic Testing
The USPSTF found adequate evidence that the benefits of risk as-
sessment, genetic counseling, and genetic testing are moderate in
women whose family history is associated with an increased risk for
harmful mutations in the BRCA1/2 genes.
The USPSTF found adequate evidence that the benefits of risk
assessment, genetic counseling, and genetic testing are small to none
in women whose family history is not associated with an increased
risk for harmful mutations in the BRCA1/2 genes.
Harms of Screening, Genetic Counseling,
and Genetic Testing
The USPSTF found adequate evidence that the harms associated
with risk assessment, genetic counseling, genetic testing, and in-
terventions are small to moderate.
USPSTF Assessment
The USPSTF concludes with moderate certainty that the net ben-
efit of risk assessment for increased risk of BRCA1/2 mutations, test-
ing for BRCA1/2 mutations, and use of risk-reducing interventions
outweighs the harms in women whose family or personal history is
associated with an increased risk for potentially harmful mutations
in the BRCA1/2 genes.
The USPSTF concludes with moderate certainty that the harms
of risk assessment for increased risk of BRCA1/2 mutations, testing
for BRCA1/2 mutations, and use of risk-reducing interventions out-
weigh the benefits in women whose family or personal history is not
associated with an increased risk for potentially harmful mutations
in the BRCA1/2 genes.
Clinical Considerations
Patient Population Under Consideration
This recommendation applies to women who are asymptomatic for
BRCA-related cancer and have unknown BRCA mutation status
(Figure 2). It includes women who have never been diagnosed with
BRCA-related cancer, as well as those with a previous breast, ovar-
ian, tubal, or peritoneal cancer diagnosis who have completed treat-
ment and are considered cancer free but have not been previously
tested. While this recommendation applies to women, the net ben-
efit estimates are driven by biological sex (ie, male/female) rather
than gender identity. Persons should consider their sex at birth to
determine which recommendation best applies to them.
Assessment of Risk
Mutations in the BRCA1/2 genes cluster in families, showing an
autosomal dominant pattern of inheritance in either the mothers
or fathers family. When taking medical and family history informa-
tion from patients, primary care clinicians should ask about specific
types of cancer, primary cancer sites, which family members were
USPSTF Recommendation: Assessment, Counseling, and Testing for BRCA-Related Cancer US Preventive Services Task Force Clinical Review & Education
jama.com (Reprinted) JAMA August 20, 2019 Volume 322, Number 7 653
2019 American Medical Association. All rights reserved.
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affected, and whether relatives had multiple types of primary can-
cer. Clinicians should also inquire about the age at diagnosis, age
at death, and sex of affected family members, both immediate
(ie, parents and siblings) as well as more distant (ie, aunts, uncles,
grandparents, and cousins).
For women who have family members with breast, ovarian,
tubal, or peritoneal cancer or have a personal history of these types
of cancer, primary care clinicians may use appropriate brief familial
risk assessment tools to determine the need for in-depth genetic
counseling. Tools evaluated by the USPSTF include the Ontario Family
History Assessment Tool (Table 1), Manchester Scoring System
(Table 2), Referral Screening Tool (Table 3), Pedigree Assessment
Tool (Table 4), 7-Question Family History Screening Tool (Table 5),
International Breast Cancer Inter vention Study instrument
(Tyrer-Cuzick) (Table 6), and brief versions of BRCAPRO. Each of
these tools has been validated and accurately estimate the likeli-
hood of carrying a harmful BRCA1/2 mutation. They can be used to
guide referrals to genetic counseling for more definitive risk
assessment.28 General breast cancer risk assessment models
(eg, the National Cancer Institute Breast Cancer Risk Assessment
Tool, which is based on the Gail model) are not designed to identify
BRCA-related cancer risk and should not be used for this purpose.
In general, these brief familial risk assessment tools include
factors associated with increased likelihood of potentially harmful
Figure 1. USPSTF Grades and Levels of Evidence
What the USPSTF Grades Mean and Suggestions for Practice
Grade Definition
A The USPSTF recommends the service. There is high certainty that the net benefit is substantial. Offer or provide this service.
Suggestions for Practice
B
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.
Offer or provide this service.
C
The USPSTF recommends selectively offering or providing this service to individual patients
based on professional judgment and patient preferences. There is at least moderate certainty
that the net benefit is small.
Offer or provide this service for selected
patients depending on individual
circumstances.
D
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.
Discourage the use of this service.
I statement
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits
and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of
benefits and harms cannot be determined.
Read the Clinical Considerations section
of the USPSTF Recommendation
Statement. If the service is offered,
patients should understand the
uncertainty about the balance of benefits
and harms.
USPSTF Levels of Certainty Regarding Net Benefit
Level of Certainty Description
High
The available evidence usually includes consistent results from well-designed, well-conducted studies in representative primary care
populations. These studies assess the effects of the preventive service on health outcomes. This conclusion is therefore unlikely to be
strongly affected by the results of future studies.
Moderate
The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimate
is constrained by such factors as
the number, size, or quality of individual studies.
inconsistency of findings across individual studies.
limited generalizability of findings to routine primary care practice.
lack of coherence in the chain of evidence.
As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be large
enough to alter the conclusion.
The USPSTF defines certainty as likelihood that the USPSTF assessment of the net benefit of a preventive service is correct. The net benefit is defined as
benefit minus harm of the preventive service as implemented in a general, primary care population. The USPSTF assigns a certainty level based on the nature
of the overall evidence available to assess the net benefit of a preventive service.
Low
The available evidence is insufficient to assess effects on health outcomes. Evidence is insufficient because of
the limited number or size of studies.
important flaws in study design or methods.
inconsistency of findings across individual studies.
gaps in the chain of evidence.
findings not generalizable to routine primary care practice.
lack of information on important health outcomes.
More information may allow estimation of effects on health outcomes.
USPSTF indicates US Preventive Services Task Force.
Clinical Review & Education US Preventive Services Task Force USPSTF Recommendation: Assessment, Counseling, and Testing for BRCA-Related Cancer
654 JAMA August 20, 2019 Volume 322, Number 7 (Reprinted) jama.com
2019 American Medical Association. All rights reserved.
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BRCA1/2 mutations. These include breast cancer diagnosis before
age 50 years, bilateral breast cancer, presence of both breast and
ovarian cancer in one individual, male family members with
breast cancer, multiple cases of breast cancer in the family, 1 or
more family members with 2 primary types of BRCA-related can-
cer (such as ovarian cancer), and Ashkenazi Jewish ancestry. The
USPSTF recognizes that each risk assessment tool has advantages
and limitations and found insufficient evidence to recommend
one over another.
Genetic Counseling
The process of genetic counseling includes detailed kindred analy-
sis and risk assessment for potentially harmful BRCA1/2 mutations.
It also includes identification of candidates for testing, patient edu-
cation, discussion of the benefits and harms of genetic testing, in-
terpretation of results after testing, and discussion of manage-
ment options. Genetic counseling about BRCA1/2 mutation testing
should be performed by trained health professiona
