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Breast Disease 27 (2006,2007) 5–20 5

IOS Press

Assessing Breast Cancer Risk and BRCA1/2


Carrier Probability
Julie Culver∗ , Katrina Lowstuter and Lauren Bowling
Department of Clinical Cancer Genetics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

Abstract. By identifying individuals with an increased risk of breast cancer, health professionals can offer prevention strategies
tailored to individual risk levels. Such strategies may include early initiation of cancer screening, more frequent screening, targeted
therapeutic or behavioral interventions, or prophylactic surgery. In order to achieve clinical benefits with this approach, however,
risk assessment strategies and effective prevention measures must be available. In this article we review current knowledge about
cancer risk assessment for unaffected women and probability models for identifying individuals who are carriers of a mutation
in BRCA1 or BRCA2, the two genes most commonly implicated in hereditary breast cancer. We review BRCA1 and BRCA2
mutations in various ethnic populations and how this information factors into risk assessment. Additionally, we summarize the
current guidelines for when to make a referral to genetic services for risk assessment and evaluation.

Keywords: Breast carcinoma, BRCA1, BRCA2, cancer genetics, cancer risk assessment, probability models, hereditary breast
cancer

INTRODUCTION greater biological closeness of affected relative(s), and


earlier age of onset of cancer.
Cancer risk assessment is practiced in clinics spe- Epidemiological studies provide evidence for two
cializing in genetics as well as other health care set- general categories of risk based on family history alone:
tings. We will describe many of the tools used by ge- (1) moderate risk, typically associated with a family
netic counselors and others to evaluate breast cancer history of breast cancer in a close relative (2) high risk,
risk and determine the likelihood of hereditary breast typically associated with a family history pattern of
cancer caused by BRCA1 or BRCA2. breast cancer in two or more relatives, indicating the
inheritance of a highly penetrant breast cancer gene
mutation. Example pedigrees are shown in Fig. 1.
Features of moderate risk families include later ages
PEDIGREE-BASED RISK ASESSMENT
of onset of breast cancer (50 years and above), few rel-
atives affected, lack of ovarian cancer, and no evidence
Breast cancer has long been known to “run in fam- of autosomal dominant transmission. It is likely that
ilies.” Epidemiological studies have established fami- a large proportion of this type of familial clustering of
ly history as a major risk factor for breast and ovarian breast cancer is due to the presence of genetic traits
cancer. Relative risks associated with an affected first- that only modestly contribute to cancer risk. Similar
degree relative range from 2 to 4 (Table 1). Relative risk environmental exposures as well as gene-environment
increases with increasing numbers of affected relatives, interactions are also likely to account for some of the
risk associated with moderate family history.
∗ Corresponding
High risk families are characterized by early age
author: Julie Culver, MS, CGC, Department of
of onset of breast cancer (less than 50 years), bilater-
Clinical Cancer Genetics, City of Hope Comprehensive Cancer Cen-
ter, 1500 E. Duarte Rd. Mod 173, Duarte, CA 91010, USA. Tel.: +1 al breast cancer, multiple affected individuals, ovarian
626 256 8662; Fax: +1 626 930 5495; E-mail: jculver@coh.org. cancer at any age, male breast cancer at any age, and a

0888-6008/06,07/$17.00  2006,2007 – IOS Press and the authors. All rights reserved
6 J. Culver et al. / Assessing Breast Cancer Risk and BRCA1/2 Carrier Probability

Table 1
Empiric Risk of Cancer Based on Family History
Cancer Family History Relative Risk
Breast First degree relative with breast cancer
All ages 2.1 (95% CI 2.0–2.2)
Affected < 50 years 2.3 (95% CI 2.2–2.5)
Affected 50 years 1.8 (95% CI 1.6–2.0) [50]
Breast Sister with breast cancer at:
20–29 years 4.68 (95% CI 0.92–11.36)
30–39 years 3.28(95% CI 1.91–4.65)
40–49 years 2.56 (95% CI 1.89–3.24)
50–59 years 2.68 (95% CI 1.98–3.38)
60–69 years 1.71 (95% CI 0.98–2.44) [64,66]
Breast Second degree relative with breast cancer 1.5 (95% CI 1.4–1.6) [50]
Ovarian Breast cancer in mother or sister before age 40 SIR 1.7 (95% CI 1.3–2.1) [46]
Ovarian Parent or sibling with breast cancer OR 1.6 (95% CI 1.3–2.0) [51]
(cancer mortality)
Ovarian First degree relative with ovarian cancer 3.1 (95% CI 2.6–3.7
Daughter with ovarian cancer 1.1 (95% CI 0.8–1.6)
Sister with ovarian cancer 3.8 (95% CI 2.0–5.1)
Mother with ovarian cancer 6.0 (95% CI 3.0–11.9)
More than one affected relative (first or second degree) 11.7 (95% CI 5.3–25.9) [59]
Ovarian Second degree relative with ovarian cancer 2.5 (95% CI 1.5–4.3) [59]

pattern of autosomal dominant transmission often ap- tified in 17.3% of women with limited vs. 5.7% with
pearing to “skip” males in the family. Families with adequate family structure [71]. Some of the BRCA1/2
these characteristics are more likely to have a muta- probability models, such as BRCAPRO, do take into ac-
tion in a highly penetrant autosomal dominant cancer count family structure, (see section below on this topic)
susceptibility gene such as BRCA1 or BRCA2, com- but others do not.
pared to moderate risk families. Ductal carcinoma in The rate of de novo (non-inherited) BRCA mutations
situ (DCIS) may be part of the phenotype of hereditary is thought to be negligible, however there are rare re-
breast cancer [32,35]. A population based study found ports of such mutations in the literature [61,69].
the rate of BRCA mutation detection is similar in DCIS
and invasive breast cancer cases [16].
Of note, when breast cancer is seen in families with EMPIRIC MODELS OF BREAST CANCER
additional types of cancers, other hereditary syndromes RISK ASSESSMENT
(reviewed by Nusbaum et al. in this issue) may be the
cause of breast cancer in the family and should be con- Family history data can be utilized in various models
sidered. For example, breast, endometrial, and thyroid for predicting individual breast cancer risk. The four
cancers occurring in an autosomal dominant pattern risk models to be reviewed in this section include the
may be the result of an inherited PTEN mutation. Claus, Gail, Tyrer-Cuzick, and BRCAPRO models. A
When evaluating small families, it is particularly im- comparison of risk estimates produced by these models
portant to consider family structure and the number of is shown in Table 2; because these four risk models in-
women surviving through later ages. A single case of a corporate different risk factors, they sometimes provide
woman with early onset breast cancer who has a limited strikingly different risk estimates and may be utilized
family history due to lack of female relatives or early to provide a range of risks in the clinical setting.
age at death of female relatives may indeed have a high-
er probability of carrying a BRCA1 or BRCA2 mutation Claus (or CASH) Model
than a similarly affected woman from a large families
with many unaffected women surviving through later The Claus model estimates the probability of an un-
ages. Among 204 single breast cancer cases before affected woman developing breast cancer based on her
age 55 who underwent genetic testing of BRCA1 and family history of breast cancer [17]. This model was
BRCA2, family structure was a strong predictor of mu- derived from empiric observations in the Cancer and
tation status (P = 0.009), with BRCA mutations iden- Steroid Hormone Study (CASH) [73]. Genetic mod-
J. Culver et al. / Assessing Breast Cancer Risk and BRCA1/2 Carrier Probability 7

Table 2
Lifetime breast cancer risks for hypothetical patients, based on four risk models
Family History Claus1 [17] Tyrer- BRCAPRO3 Gail4 Notes on model limitations
Cuzick2 [67] [13,47] [29]
Case 1 40 year old woman 34% 24% 18% 19% Gail does not incorporate
– mother BC 35 maternal aunt (SDR)
– maternal aunt BC 41
Case 2 40 year old woman 23% 21% 18% 11% Gail does not incorporate
– paternal aunt BC 28 paternal (SDR) relatives
– paternal grandmother BC 39
Case 3 40 year old woman 19% 25% 23% 11% Gail does not incorporate
– mother OC 55 OC or SDRs; Claus does
– maternal aunt BC 45 not incorporate OC
– maternal grandmother BC 49
Case 4 40 year old woman of Ashkenazi Jewish 19% 31% 30% 11% Same as Case 3; addition-
ancestry ally, Gail and Claus do not
– mother OC 55 incorporate AJ ancestry
– maternal aunt BC 45
– maternal grandmother BC 49
BC = Breast cancer, OC = ovarian cancer, SDR = second-degree relative, AJ = Ashkenazi Jewish.
1 Claus model calculates breast cancer risk to age 79 years.
2 Tyrer-Cuzick model calculates lifetime breast cancer risk to an unspecified age. Other personal characteristics included in the model for each

case were: age at menarche = 12, age at first birth = 28, height = 1.37 meters (5 feet, 4 inches), weight = 61 kg (134 lbs), woman has never
used HRT, no atypical hyperplasia or LCIS.
3 BRCAPRO calculates breast cancer risk to age 85 years.
4 Gail model calculates breast cancer risk to age 90. Other personal characteristics included in the Gail risk model for each case were: age at

menarche = 12, age at first birth = 28, breast biopsies = 0, race = White.

els were developed to fit the age-specific incidence of rent age, to appropriately reduce her risk due to having
breast cancer among first- and second- degree relatives passed some of her years of breast cancer risk. For ex-
of 4730 Caucasian breast cancer cases and 4688 Cau- ample, in Table 2, Case 1, the 40 year old woman with a
casian controls, aged 20–54 years. Although the Claus 34% lifetime risk of breast cancer should have her risk
model is based on an assumption that risk associat- re-calculated if she ages and does not develop breast
ed with a family history can be exclusively attributed cancer; at age 50 the Claus model would predict a 28%
to rare autosomal dominant mutations with high pene- lifetime risk. Another approach to making the adjust-
trance, which is almost certainly incorrect, the results ment for current age is to use the software available to
of this model agree with observations concerning the calculate Claus risks on a Palm pilot [1], which makes
association of family history and breast cancer risk. For calculating these risks very simple. Also, the same ad-
any given unaffected female patient, the model incor- justment to the Claus model is made by CancerGene
porates up to two relatives affected with breast cancer (BRCAPRO) program, discussed below (downloadable
(first- or second- degree) and the decade of onset of from link in Table 3).
breast cancer for each relative. The model provides
risk estimates for each decade of the patient’s life up to Tyrer-Cuzick Model
age 79. However, the Claus model does not incorpo-
rate family size, ethnic background, or other risk fac- The Tyrer-Cuzick model [67] incorporates the prob-
tors. Therefore, it may not be not suitable for women ability of a BRCA1 or BRCA2 mutation, the likelihood
with more than two affected relatives, as it may un- of a low penetrance gene mutation, and personal risk
derestimate risk. Furthermore, the Claus model does factors. For an individual unaffected woman, family
not include incorporate relatives with ovarian cancer. history is used in conjunction with Bayes’ theorem to
A separate Claus paper allows for the calculation of produce the likelihood of a BRCA mutation. The asso-
breast cancer risk for women with a first-degree family ciated breast cancer risk is then calculated and modified
history of ovarian cancer [18]. to reflect the relative risk associated with the woman’s
Claus risk estimates are easily calculated using the personal risk factors. Personal risk factors included
published tables in the original paper [17]. However, are: current age, age at menarche, parity, age at first
one adjustment must be made using a formula on page livebirth, age at menopause, history of atypical hyper-
645 of the paper, which accounts for the patient’s cur- plasia or lobular carcinoma in situ, height, and body
Table 3 8
BRCA Probability Models
Model Output Risk Determinates Limitations How to use
Couch [19]/ Couch Couch Couch Couch
Penn II * BRCA1 probability * AJ * Only affected family members included * Published table [19]
(under review) Penn II * BC/OC in FDR/SDR * Does not consider degree of relationship to cal- * CancerGene program at web site:
* BRCA1/2 probability * Average age of onset of culate mutation probability. http://www3.utsouthwestern.edu/cancergene/cancergene.htm
BC in family * Mutation probability applies to all affected family Penn II
Penn II adds: members. Web site:
* Male BC * BRCA2 risk not generated unless modified http://acgh.afcri.upenn.edu/cgi-bin/bcm/bcm.pl
* Pancreatic cancer Penn II
* Prostate cancer * Unclear at this time. Data is under review
* Bilateral breast cancer (personal communication)
Myriad [27] * BRCA1/2 probability * AJ * Data set based on test requisition forms complet- * Table on Myriad web site:
* BC < 50 years in ed by clinicians (subject to errors and potentially http://www.myriadtests.com/provider/brca-mutation-
FDR/SDR incomplete) prevalence.htm
* OC in FDR/SDR * Does not consider family structure and unaffected * Computer/ palm pilot software available at the same site
* Personal history BC, OC, relatives * CancerGene program at web site:
and male BC any age * Does not include other BRCA related cancers http://www3.utsouthwestern.edu/cancergene/cancergene.htm
BRCAPRO * BRCA1/2 probability * AJ * Need to input all family members (affected and * CancerGene, version 4.3, at web site:
[13,47] * Risk of BC and OC * BC/OC in FDR/SDR unaffected) in order to do Bayesian calculation http://www3.utsouthwestern.edu/cancergene/cancergene.htm
* Bilateral breast cancer * Progeny pedigree software package [5]
* Male BC
* Mutation status in family
Tyrer-Cuzick [67] * AJ * Only applies to unaffected individuals * Computer model Tyrer-Cuzick (IBIS Breast Cancer Risk
* BC/OC in FDR/SDR Evaluation Tool, RiskFileCalc version 1.0, copyright 2004),
* Personal risk factors (see available by contacting ibis@cancer.org.uk
text)
Manchester [22] * Whether family meets * BC/OC in FDR/SDR * Does not provide an exact probability of a muta- * Published scoring system [22]
10% likelihood of a mu- * Male BC tion
tation in BRCA1/2 * Pancreatic cancer * Not applicable to AJ families
* Prostate cancer
J. Culver et al. / Assessing Breast Cancer Risk and BRCA1/2 Carrier Probability

BOADICEA [8] * BRCA1/2 probability * BC/OC in FDR/SDR * Does not take into account possibility of a BRCA1 * BOADACIA pedigree software is currently undergoing beta
* Risk of BC and OC * Mutation status in family and BRCA2 mutation in same individual testing; updates will be available on web site:
http://www.srl.cam.ac.uk/genepi/boadicea/boadicea home.
html
Key BC = Breast cancer, OC = ovarian cancer, FDR = first-degree relative, SDR = second-degree relative, y = years, AJ = Ashkenazi Jewish BC = Breast cancer, OC = ovarian cancer,
FDR = first-degree relative, SDR = second-degree relative, y = years, AJ = Ashkenazi Jewish
J. Culver et al. / Assessing Breast Cancer Risk and BRCA1/2 Carrier Probability 9

Table 4
BRCA1/BRCA2 carrier probability estimates for hypothetical patients, based on five models
Case Family History Modified Myriad BRCA- Tyrer- Manchester Notes on models
Couch1 PRO Cusick2
1 40 year old women with BC3 N/A 7% 2% N/A BRCA1 score = 3 – Couch is not designed to calcu-
– 3 older unaffected sisters4 BRCA2 score = 3 late probability for a single affected
Does not meet 10% individual
threshold – BRCAPRO considers the unaf-
fected sisters
2 50 year old women with BC at 88% 55% 88% N/A BRCA1 score = 15 – BRCAPRO considers the moth-
40 and OC at 50 BRCA2 score = 12 if er’s early death
– Mother deceased at 40 BRCA1 negative – Risk estimates are high because
accident Meets 10% threshold for of BC and OC in a single individual
– Mat aunt BC 35 both genes
3 51 year old women with BC3 4% 3% 8% N/A BRCA1 score = 6 – BRCAPRO may overestimate risk
– Mother BC 52 BRCA2 score = 6 as unaffected relatives (if any) were
– Mat aunt BC at 56 Does not meet 10% not entered
threshold
4 −35 year old 21% 12% 10% 4% – BRCA1 score = 15 – Risks are approximately double
unaffected woman5 BRCA2 score = 12 if for the patient’s sister
– Sister BC 40 BRCA1 -negative
– Pat aunt OC 55 Meets 10% threshold for
both genes
5 −35 year old unaffected 44% 27% 36% 25% Model does not apply to – In comparison to Case 4, each
woman5 of Ashkenazi AJ population model shows a higher probability
Jewish ancestry with AJ ancestry.
– Sister BC 40 – Manchester does not apply to AJ
– Pat aunt OC 55 population
BC = Breast cancer, OC = ovarian cancer, AJ = Ashkenazi Jewish.
1 Probabilities are derived from modifying Couch to include BRCA1 and BRCA2 probability of a mutation (see description of modification in the

text); Couch model is not used for Case 1 because the model does not apply to single cases.
2 Tyrer-Cuzick model cannot be used for Cases 1–3 because it is only applicable to unaffected patients. See Table 2, footnote 2 for personal

characteristics of Cases 4 and 5 included in Tyrer-Cuzick model.


3 Age of women equals age of diagnosis with cancer.
4 Ages of sisters entered into to BRCAPRO was 50, 55, and 60 years of age.
5 Risk is for the unaffected patient. For the Couch model, this represents 50% of the family risk calculated, modified to include BRCA2 as

discussed in the text.

mass index (BMI). This is a statistical model based Gail Model


on combining relative risks, and not an actual sample
of women. The model has been incorporated into a The Gail model [29] estimates the probability of an
computer program, which produces very user-friendly unaffected woman developing breast cancer over spec-
outputs of both the likelihood of the patient developing ified time intervals based on her age and personal risk
breast cancer as well as the probability of the patient factors. It was developed using data from a nested case-
carrying a BRCA mutation (Table 3). control subset of the 284,780 women participating in
the Breast Cancer Detection and Demonstration Project
BRCAPRO Model
(BCDDP) [11]. These were predominately Caucasian
The BRCAPRO model [13,47] provides risk esti- women 35 to 79 years of age, receiving annual mam-
mates for breast and ovarian cancer based on the likeli- mography screening. The model includes risk factors
hood that a person carries a BRCA1 or 2 mutation. Us- that were important predictors of risk in the BCDDP
ing a patient’s current age, cancer history, and family and was derived from an unconditional logistic regres-
history of breast and ovarian cancer in first- and second- sion analysis. Risk factors (and their associated codes)
degree relatives, the program uses Bayesian analysis include: age [<50; 50], age at menarche [14; 12–
to calculate the probability of a BRCA mutation, and 13; <12], age at first live birth [<20; 20–24; 25–29;
from that probability, the risk of breast and ovarian can- 30; or nulliparous;], number of previous breast biop-
cer. See detailed discussion of the BRCAPRO model sies [0; 1; 2] and whether any biopsy found atypical
in the section on BRCA probability and related models, hyperplasia (yes, no), and number of first-degree rela-
below. tives (mother or sisters) with breast cancer [0; 1; 2].
10 J. Culver et al. / Assessing Breast Cancer Risk and BRCA1/2 Carrier Probability

(a) second-degree and paternal relatives are not included in


the risk calculation. Therefore, we do not recommend
its use for evaluating patients with a significant family
history of breast cancer. However, the Gail model is an
Br, 42
d. 43
effective clinical tool in determining whether a patient
meets a minimum risk threshold to be offered tamoxifen
for chemoprevention. This risk threshold was the entry
criteria of the BCDDP trial and was equal or greater
Ov, 53
Br, 50; Br, 68 d. 56
than the risk of a an average 60-year old woman, which
is equivalent to a 5 year predicted risk of breast cancer of
at least 1.66% [25] For breast cancer risk estimation in
clinical practice, the Gail model is most appropriate for
Br, 40 Br, 35 women with affected first-degree relatives or women
with a history of biopsies. Both Palm Pilot [3] and web
(b) versions [2] are available, and the Gail model is also
available in CancerGene (BRCAPRO), with web link
shown in Table 3.
Validation studies have been performed on the origi-
nal Gail model, which demonstrated that in some cases
Br, 68 it failed to accurately predict cancer risk. Two stud-
ies found the Gail model overpredicted the absolute
risk of breast cancer in women less than age 60 who
did not undergo annual mammography screening [14,
57]. Additionally, the model tended to overpredict risk
for women less than age 60 and underpredict risk for
women over age 60 [14].
It is important to note that risk estimates for the same
woman using either the Claus and Gail models may not
Br, 52
be identical, in part based upon the different parameters
of the models. Indeed, when looking at large numbers
of women with a family history, Gail estimates tend to
be higher than Claus estimates [39,40].
Fig. 1. Example pedigrees illustrating a high and moderate risk breast
cancer families.
Although no risk assessment model is appropriate
for every patient, clinicians often choose one model
The Gail model determines an odds ratio for a given over another for different types of patients. Patients
woman to develop breast cancer and combines this with with a significant family history of breast cancer in
baseline age-specific hazard rates and competing mor- second degree relatives should not be evaluated with the
Gail model (Table 2). However, patients with a biopsy
tality risks, resulting in an absolute risk of breast can-
history, especially a biopsy with atypical hyperplasia,
cer over specified time intervals. Later, the National
may best be evaluated with the Gail model. The Gail
Surgical Adjuvant Breast and Bowel Project’s Breast
and Claus models should be used with caution if ovarian
Cancer Prevention Trial modified the Gail model to
cancer is present in the family. The Tyrer-Cuzick and
incorporate race and include daughters as first-degree BRCAPRO models can incorporate Ashkenazi Jewish
relatives [25]. ancestry, while Gail and Claus cannot. Additionally,
When using the Gail model for breast cancer risk BRCAPRO can account for the size and structure of the
assessment, it is important to consider the limitations of patient’s family and current age of family members. In
this model. The Gail model is inadequate for evaluating the clinical setting, a patient can be provided with a
family history because it does not incorporate second- range of risk estimates from the models that are deemed
degree relatives (including aunts, grandmothers, or any appropriate for her circumstance. Providing the range
paternal relatives) or the age of onset of breast cancer will also enable the patient to see that risk estimation
in any relative. For example, Cases 2, 3, and 4 in is an imprecise science. Based on an assessment of
Table 2, the Gail model does not calculate increased risk the risk numbers provided, screening and prevention
of breast cancer attributable to family history because programs can then be tailored individually.
J. Culver et al. / Assessing Breast Cancer Risk and BRCA1/2 Carrier Probability 11

BRCA 1/2 Probability and Related Models cer or bilateral female breast cancer. The model is
further limited as it predicts for BRCA1 mutation sta-
There are numerous models now available to esti- tus only and the study population consisted mainly of
mate the probability of an individual having a mutation Caucasian women. In clinical practice, the Couch may
in BRCA1 and BRCA2 genes. A few of these models be modified to include BRCA2 mutation probability by
also predict individual cancer risks. (Table 3) Some of multiplying the estimated BRCA1 mutation probability
these models were first developed around 1997, soon by a factor of 1.33. The modification by a factor of 1.33
after BRCA clinical genetic testing became available. accounts for the contribution of BRCA2 to the over-
However, the field of mutation and cancer risk proba- all load of hereditary breast cancer due to BRCA1 and
bility modeling continues to evolve as evidenced by the BRCA2 mutations and is based on the published data
recent revision of the Couch model and publications of from the combined analysis for the original cohort [56].
new models such as BOADICEA. The same research team from the University of Penn-
sylvania Abramson Cancer Center that developed the
Couch Model original Couch model has recently revised and updat-
ed the model, entitled “Penn II,” to predict for both
The Couch model, published by Couch et al. in 1997, BRCA1 and BRCA2 mutations and to consider other
is a widely used logistic regression model that predicts personal and family cancer history (Table 3). The mod-
the probability of a BRCA1 mutation in a given fami- el takes into account three generations of breast and
ly [19]. The purpose of Couch et al.’s original publica- ovarian cancer (e.g. including cousins) as well as oth-
tion was to define the incidence of BRCA1 mutations in er BRCA-associated cancers including pancreatic and
women with breast cancer who were referred for breast male specific cancers (prostate and male breast cancer).
cancer risk assessment. Couch et al. gathered personal The development and validation paper for the Penn II
cancer history, family history of cancer, and blood from model is currently under review [58].
263 women with breast cancer seen for cancer risk as-
sessment between 1993 and 1995. The Couch model is Myriad
presented in a table format within the publication [19].
The model utilizes personal and family history of breast The mutation prevalence tables published by Myri-
and ovarian cancer in first and second-degree relatives ad Genetic Laboratories provide easily accessible risk
to estimate the mutation probability. The model also estimates for detecting a BRCA mutation. These tables
considers Ashkenazi Jewish ancestry. An average age are based on methods published by Frank et al. [27].
of onset of breast cancer in the family is used to gen- The risk estimates presented were originally derived
erate the mutation probability, (age of onset of ovarian from BRCA clinical test results over a three year period
cancer is not included in the average age calculation). from 10,000 individuals with a personal and/or family
The risk provided is the family’s probability of a BRCA1 history of breast and/or ovarian cancer. Of these in-
mutation and applies to all affected (diagnosed with dividuals, 7,461 had full gene sequencing of BRCA1
breast or ovarian cancer) family members. The proba- and BRCA2 and 2,539 were screened only for the three
bility of a mutation in unaffected first-degree relatives Ashkenazi Jewish founder mutations. Approximately
of breast/ovarian cancer patients is half of the family’s 90% of individuals tested were women and ∼45% had
probability for carrying a mutation. For example, if a a personal history of breast cancer only. The recently
Couch mutation probability is 10% for a family, then updated mutation prevalence tables, released on the in-
the daughter of an affected individual in the family has ternet by Myriad in March of 2006, (Table 3) are based
a 5% chance of having a BRCA1 mutation, as she has on clinical test results from ∼49,000 individuals who
a 50% chance of inheriting the mutated allele from her had full gene sequencing and ∼15,000 individuals who
mother. The model can be applied by using the table in were screened for the three Ashkenazi Jewish founder
the original paper [19] and in the CancerGene program mutations.
(Table 3). The benefits and limitations of the Myriad mutation
The limitations of the Couch model should be con- prevalence tables should be considered when provid-
sidered when being applied to a clinical setting. The ing mutation risk estimates in the clinical setting. The
model does not account for other types of cancer as- greatest advantage of using these tables is that the risk
sociated with the BRCA genes aside from breast and estimates are based on a large clinical sample and cat-
ovarian cancer and does not consider male breast can- egorized by Ashkenazi Jewish versus non-Ashkenazi
12 J. Culver et al. / Assessing Breast Cancer Risk and BRCA1/2 Carrier Probability

Jewish ancestry. In addition, these tables are easy to ability, the pedigree must be entered, which can be
use and updated frequently. The tables are available for time-consuming. Another limitation of this model is
download on palm pilot (Table 3) and the risk numbers the penetrance data used to derive the model were tak-
are produced by the CancerGene program (Table 3). en mainly from Caucasian families therefore its use in
However, the risk estimates presented in these tables non-Caucasian families may be limited.
do not take into account: the specific age of onset of Validation studies were conducted in 2002 by com-
breast cancer, the number of affected relatives, bilater- paring the estimated probability of carrying a BRCA
al breast cancer, unaffected relatives, or other BRCA- mutation as computed by BRCAPRO to actual genetic
associated cancers. There is also no distinction be- test results. These studies found that BRCAPRO gives
tween first and second degree relatives or maternal ver- an accurate measurement of the probability of a muta-
sus paternal affected relatives. The Ashkenazi Jewish tion and therefore is a useful instrument in the counsel-
tables also include some women who had testing for ing process [12].
the three founder mutations because of a known muta-
tion in the family, and the numbers in the table could Tyrer-Cuzick Model
be an overestimate. Furthermore, these risk estimates
are entirely dependent upon the personal and family The Tyrer-Cuzick breast cancer risk assessment
history information provided on test requisition forms model (discussed in detail above) [67] also calculates
completed by the ordering clinician, which is subject BRCA mutation probabilities. This model incorporates
to errors and omissions by health care providers. In first and second- degree gamily members with breast
summary, these tables are widely used in the clinical and ovarian cancer and their ages of onset. However, a
setting to provide risk estimates prior to BRCA testing, disadvantage is that the model calculates the mutation
but the tables may under- or over-estimate the risk of probability only for an unaffected individual, which
detecting a BRCA mutation in some families and should is usually not the ideal candidate for initiating testing
be interpreted with caution. within a family. Software is available to calculate risks
(Table 3) and a user-friendly printout is produced.
BRCAPRO
Manchester Model
BRCAPRO is a mathematical model that predicts the
probability of a BRCA mutation [13,47]. The founda- The Manchester Model is a scoring system that will
tion of this model uses Mendelian genetics and Bayes’ determine whether a family has  10% probability of
theorem to evaluate a family history of cancer for mu- a mutation in either BRCA1 or BRCA2 [22] or a 20%
tation probability. Specifically this model predicts combined risk [23]. This model was developed in
the probability having a mutation in either gene, both Manchester, England using a population of 422 non-
genes, or neither gene [12]. The model also estimates Ashkenazi British individuals. Using this population
breast and ovarian cancer risk, as described above. The the authors designed a scoring system to determine
model incorporates all family members (up to second- whether a family may have a deleterious BRCA1 or
degree relatives), their history of breast and ovarian BRCA2 mutation. The cancers included in the scoring
cancer, bilateral breast cancer, male breast cancer, and system are female breast cancer, male breast cancer,
whether the family has Ashkenazi ancestry. Mutation ovarian cancer, pancreatic cancer, and prostate cancer.
probabilities can be calculated for both affected and Between 1 and 8 points are given for each cancer di-
unaffected individuals; however, cancer risk estimates agnosis, depending on type of cancer and age of onset.
only apply to unaffected individuals. The model also Higher scores are given for earlier ages of onset, and
takes into account mutation status in the family (i.e., if the decade of diagnosis is included in calculating the
a family member has tested negative for BRCA muta- score for breast cancer cases. For ovarian, male breast,
tion). and pancreatic cancer cases, a distinction of diagnosis
The model can be downloaded for free as part of before or after age 60 is made. Separate scores are cal-
CancerGene (Table 3) and is also available as part of culated for BRCA1 and BRCA2 and a total score of 10
the Progeny pedigree software package [5]. Cancer- for one lineage in a family is equivalent to a 10% prob-
Gene Version 4.3 accounts for whether a woman had an ability of a mutation in that gene. For example, female
oophorectomy. The output is easy to interpret; howev- breast cancer diagnosed <30 years is given a score of
er, in order to obtain the most accurate mutation prob- 6 for BRCA1 and 5 for BRCA2; ovarian cancer <60
J. Culver et al. / Assessing Breast Cancer Risk and BRCA1/2 Carrier Probability 13

Table 5
is given a score of 8 for BRCA1 and 5 for BRCA2 (if
Selected examples of recurrent and founder mutations in the BRCA
BRCA1 has already been tested). Therefore, a family genes
with one case of breast cancer before age 30 and one Population BRCA1 BRCA2
case of ovarian cancer before age 60 is given a total Ashkenazi Jewish 185delAG 6174delT
BRCA1 score of 14 and a BRCA2 score of 10 (if BRCA1 5382 ins C
testing is negative). Thus testing is justified for this Icelandic 999del15
family, with BRCA1 testing to be done prior to BRCA2 British 6-kb dup exon 13
4184 del4
testing. Using this model, the gene with the higher Dutch 2804delAA
score (over 10) may be tested first; if no mutation is del exon 13
found in that gene, scores may be subsequently adjust- del exon 22
ed for the other gene. This model does not suggest that Chinese 1081delG
African American 943ins10
mutation analysis is justified in an isolated breast or 1832del5
ovarian cancer case at any age. 5296del4
An important advantage of the Manchester model is Hispanic 185delAG
del exon 9–12
that the scoring system can be easily used in the clini-
French Canadian 4446C>T 8765delAG
cal setting and does not require the use of software or 2953del3 + C 2816insA
the input of an entire pedigree into a computer. Ad- 3768insA 6085G>T
ditionally, validation studies by the authors compared 6503delTT
the Manchester model against BRCAPRO, Couch, and
Myriad and found the Manchester model to outperform the BRCA1 and BRCA2 genes are assigned to poly-
the other models in discriminating families with a 10% genic factors. In 2005, the model was found to ac-
likelihood of a mutation [22]. curately predict the carrier probability in individuals
An important limitation of this model is that it does of French Canadian ancestry [6]. The researchers are
not calculate the exact probability of a mutation, but developing a web-based software interface, which en-
rather distinguishes whether a family meets the 10% ables clinicians to enter pedigree information to deter-
or 20% probability cutoff or not. This model may not mine probability information. Updates on this software
be as useful in a clinic that uses a different probability can be obtained by checking the BOADICEA web site
cutoff or does not use any specific numerical probability (Table 3). One can also utilize the published tables [8]
cutoff for offering BRCA testing. Also, the model is to assess risk.
not designed for use in Ashkenazi Jewish individuals. In clinical practice, using multiple BRCA probability
models is time consuming and therefore it may be best
BOADICEA to choose a model or two that best suit the patient. We
have indicated some of the benefits and limitations of
The BOADICEA model was developed by Antoniou each model in Tables 3 and 4. Additionally, Table 4
et al. in 2002 in order to predict the probability of a shows the probability estimates produced by each avail-
BRCA1 or BRCA2 mutation and provide breast and able model for various pedigrees. Of note BOADICIA
ovarian cancer risks [6–8]. The model was devel- was not included in this table as the software needed to
oped using complex segregation analysis of the occur- use the model is not available at this time.
rence of breast and ovarian cancer in two data sets Here are some considerations of when to use the
(population based series of 1484 breast cancer cases published models discussed above. These comments
and 156 multiple case families). Both data sets were are based on our clinical practice and others may have
ascertained from probands with breast cancer, main- differing viewpoints. The Couch model should not be
ly from the United Kingdom. The model takes in- used when there is only a single case of breast or ovar-
to account that familial breast cancer is explained by ian cancer in a family since the probability table in the
both BRCA1 and BRCA2 mutations as well as a poly- original article is based on families with multiple af-
genic component (reflecting the joint multiplicative ef- fected individuals. In families with multiple affected
fect of multiple genes of small effect on breast cancer relatives, the Couch model estimates should be modi-
risk). Furthermore the model accounts for the possi- fied to include BRCA2 probabilities, as explained in the
bility of genetic modifiers, which may affect the pene- section on the Couch model above. The Myriad model
trance of BRCA1 and BRCA2 mutations. The remain- is useful for both single cases and families; this mod-
ing clusters of cancer in families not accounted for by el is extremely quick to calculate probability estimates
14 J. Culver et al. / Assessing Breast Cancer Risk and BRCA1/2 Carrier Probability

Table 6
Published guidelines for referral to cancer genetics services
Non-Ashkenazi Jewish Ashkenazi Jewish
Affected National Comprehensive Cancer Network (United States) National Comprehensive Cancer Network
*BC  50y# (United States)
*Two primary HBOC cancers in an individual (bilateral breast cancer and *Less stringent than for non-Ashkenazi
breast and ovarian cancer) Jewish
*Two breast primaries or breast and ovarian cancers in close relatives) on the
same side of the family
*Clustering of breast cancer with male breast cancer, thyroid cancer, sarco-
ma, adrenocortical carcinoma, endometrial cancer, pancreatic cancer, brain
tumors, dermatologic manifestations or leukemia/lymphoma on the same side
the family
*Member of a family with a known mutation in breast cancer susceptibility
gene
*Male breast cancer
*Clustering of ovarian cancer
Unaffected United States Preventive Services Task Force United States Preventive Services Task Force
*Two FDR with BC, with one diagnosed <50y *Any FDR with BC or OC
*Combination of 3 FDRs or SDRs diagnosed with BC regardless of age *Two SDR on the same side of the family
*Combination of both BC and OC among FDR and SDR with BC or OC
*FDR with bilateral BC
*Combination of 2 or more FDR or SDR with OC National Institute for Health And Clinical
*Single FDR or SDR having both BC and OC Excellence (United Kingdom)
*Male BC in any relative *Seek advice from tertiary care contact about
levels of risk and appropriateness of referral
National Institute for Health And Clinical Excellence (United Kingdom)
*Two FDR with BC, diagnosed before average age 50y
*Three FDRs or SDRs, diagnosed before average age 60y
*Four relatives diagnosed at any age (including at least 1 FDR)
*Combination of one OC in any relative and:
– FDR or SDR with BC < 50
– Another OC
– Two FDR or SDR with BC, diagnosed before average age 60y
*Bilateral BC in a FDR diagnosed before average age 50y
*Bilateral BC in a FDR or SDR and one FDR or SDR with BC diagnosed
<60y
*Male BC in any relative and:
– FDR or SDR with BC diagnosed <50y
– Two FDRs or SDRs diagnosed with BC before average age 60y
Key BC = Breast cancer, OC = ovarian cancer, FDR = first-degree relative, SDR = second-degree relative, y = years.
# Includes both invasive and ductal carcinoma in situ.

and we find it very useful in the clinic. BRCAPRO model does not calculate. The Manchester model is
model is often useful if a family is particularly large useful in a setting of limited resources when a muta-
or small because its Bayesian analysis considers family tion probability of 10% is used as a threshold for offer-
size. Additionally, the model is useful if genetic testing ing genetic testing. Finally, it is important to remem-
has been performed in the family and is negative, but ber that none of the risk models was developed from
one wishes to calculate the probability of a mutation in non-Caucasian populations.
other family members. Finally, BRCAPRO is the only When sharing these probability estimates with pa-
published model currently available that incorporates tients, providing a range of numbers may be helpful
bilateral breast cancer. to illustrate that the likelihood of a mutation may vary,
The Tyrer-Cuzick model is only applicable to unaf- depending on the factors considered in their family. In
fected women. A nice feature of this model is that it many cases, the probability of a mutation is not criti-
provides both a breast cancer risk estimate and a BRCA cal to the decision to undergo testing, because of how
mutation probability estimate; however, when possible, critical the results of testing can be. Results will often
it is almost always most informative to test an affect- influence medical management, such as whether a pa-
ed family member first, so a probability estimate may tient should undergo an oophorectomy or more inten-
be needed for that individual, which the Tyrer-Cuzick sive breast cancer surveillance.
J. Culver et al. / Assessing Breast Cancer Risk and BRCA1/2 Carrier Probability 15

Giving a patient probability estimates often sets an geographic diversity and frequency of this mutation.
expectation for the likelihood the test will be positive. This group concluded that the Exon 13 duplication is
A patient who has a very low probability of a mutation likely a founder mutation in countries that have a his-
who is insistent upon having genetic testing may be torical link to Great Britain. Another high frequency
convinced that testing is not worthwhile if the proba- mutation identified within the British population is the
bility of finding a mutation is very low (additionally, BRCA1 4184del4 mutation. Because different haplo-
her insurance company may not cover the cost of test- types have been identified with the 4184del4 mutation
ing and seeing her probability estimate may help her it is unlikely to be a true founder mutation; most likely,
understand why that is the case.) it is a highly recurrent mutation found in the United
Kingdom [24]. In 1997, Peelen et al. characterized the
2804delAA BRCA1 Dutch founder mutation as origi-
RISK ASSESSMENT IN SPECIFIC nating 32 generations ago in the Dutch population [48].
POPULATIONS Within the Dutch population, large deletions of exon
13 and 22 in BRCA1 have also been characterized as
In the overall population the incidence of BRCA founder mutations [49]. Although there have been few
mutations varies in the literature from approximately studies of BRCA mutation prevalence in Asian popula-
1/500–1/1100 [4]. Higher allele frequency of BRCA tions, a number of founder mutations have been iden-
mutations in specific populations is due to founder ef- tified to date. One of these mutations, the 1081delG
fect or recurrent mutations. 1 The most well-known and mutation in BRCA1, was described as a likely founder
prevalent founder effect in BRCA genes occurs with- mutation in China by Khoo et al. in 2002 [37].
in the Ashkenazi Jewish population. Approximately Even within a single country, individuals of differ-
95% of all hereditary breast cancer within the Ashke- ent ethnic backgrounds have founder mutations. In
nazi Jewish population is attributed to three founder the United Sates, approximately 12% of the popula-
mutations: 185delAG and 5385insC in BRCA1 and tion is of Hispanic ancestry. In a clinic based cohort
6407delT in BRCA2. Approximately 1 in 40 (2.5%) study of primarily Mexican Hispanic individuals seen
individuals of Ashkenazi Jewish ancestry is a carrier for breast cancer risk assessment, 4 out of 110 (3.6%)
of one of these three BRCA mutations [53]. This is had the BRCA1 185delAG mutation [72]. Interestingly,
dramatically higher than the frequency in the general the 185delAG mutation found in these individuals had
Caucasian population. the same haplotype as the Ashkenazi Jewish founder
Other populations also have founder effects or recur- haplotype. None of the four unrelated Hispanic pa-
rent mutations. For example within the Icelandic pop- tients with the 185delAG mutation had any knowledge
ulation a single BRCA2 mutation (999del5) accounts of Jewish ancestry. This may be the result of the Jewish
for a high proportion of familial breast cancer [33,65]. population in Spain during the Spanish Inquisition be-
Some founder mutations, such as the exon 13 duplica- ing forced to convert to Christianity or they would have
tion, have been identified across geographically diverse been expelled from the country. Many of the conver-
populations who originate from a common background. sos (Jews converted to Christianity) and crypto-Jews
In 1999, a BRCA1 exon 13 duplication was identified (conversos who secretly practiced Judaism) may have
and found in one Portuguese family and three appar- migrated to the United States carrying with them the
ently unrelated families of European ancestry from the 185delAG BRCA1 mutation. Also in 2005, Weitzel et
United States; via haplotype analysis, these families al. identified an apparent founder rearrangement mu-
appeared to be from a common ancestor. In 2000, tation within the Mexican Hispanic population involv-
the Exon 13 duplication Group set out to estimate the ing a deletion of exons 9–12. This was identified in
three apparently unrelated families [70]. There are also
documented founder mutations identified in families of
1 Founder effect is defined as a high frequency of a mutated allele
African ancestry in America. For example the BRCA1
in a population, which was founded by a small group where member
of the group was a carrier of the mutated allele [43]. Individuals 943ins10 was described in 1999 as being associated
who carry the same founder mutation also share common markers with a single haplotype in five families of African an-
within the gene or adjacent to the gene (same haplotype). Recurrent cestry from different geographic locations (three from
mutations are commonly seen mutations that do not segregate with
the United States, one from the Ivory coast and one
the same markers (i.e. have different haplotypes) among different
carriers. These mutations are likely due to areas within the gene from the Bahamas) [41]. This mutation has been de-
prone to mutation or ‘hot spots.’ scribed as an ancient founder mutation of West African
16 J. Culver et al. / Assessing Breast Cancer Risk and BRCA1/2 Carrier Probability

origin of a similar age to the 185delAG founder mu- approximately 5% of hereditary breast cancer in the
tation in the Ashkenazi Jewish population [45]. There Ashkenazi Jewish population is caused by non-founder
have also been two other BRCA1 recurrent mutations mutations [36,55]. When a founder mutation has been
described in the literature in African American fami- identified in an Ashkenazi Jewish family, testing at-
lies: BRCA1 5296del4 and BRCA1 1832del5 [30]. One risk family members should include evaluation for the
challenge in interrupting BRCA genetic test results in other two-founder mutation, as there have been numer-
individuals of African ancestry is the high rate of vari- ous reports of families segregating with more than one
ants/polymorphism identified within African Ameri- founder mutation [28,38].
cans compared to Caucasian Americans [45]. Interpre- Furthermore, knowledge of these mutations helps to
tation of these variants of uncertain significant is cov- estimate the likelihood of a BRCA mutation. For exam-
ered in more detail in the Brown et al. article in this ple, in the Ashkenazi Jewish population, the likelihood
issue. of being a carrier of a BRCA mutation is higher due to
In other parts of North America there are other pop- the relatively high frequency of the three founder muta-
ulations with a high rate of founder mutations. For tions and therefore the threshold of when to offer genet-
example there are seven founder mutations within the ic testing is lower than in the general Caucasian popula-
BRCA genes which account for a significant proportion tion. Many of the mutation probability models detailed
of the hereditary breast and ovarian cancer in individ- previously consider Ashkenazi Jewish ancestry for
uals of French ancestry in Canada [62]. Of these sev- BRCA mutation probability calculations. Knowledge
en mutations two occur more frequently than the oth- of founder and recurrent mutations leads to more ac-
ers, BRCA1 4446C>T and BRCA2 8765delAG [15]. curate risk estimation, cost effective mutation-targeted
A complete list of the seven founder mutations can be testing, and guides appropriate testing for when to offer
found in Table 5. These mutations are so common that rearrangement analysis or other testing methodologies.
often individuals of French Canadian ancestry initiate
testing of the BRCA genes with a panel of the founder
mutations and if negative then consider reflex to com- LOW PENETRANCE GENES
plete evaluation of the genes. This testing strategy is
comparable to that used for individuals of Ashkenazi Germline mutations in high-penetrance breast cancer
Jewish ancestry. susceptibility genes (BRCA1, BRCA2, p53, and PTEN)
Knowledge of the numerous recurrent and founder are rare in the general population and only account
mutations in BRCA1 and BRCA2 genes have important for approximately 5–10% of all breast cancers [21,26,
implications for risk assessment and clinical care. In 44]. On the other hand, variants in low-penetrance
countries such as Iceland where a single BRCA2 muta- breast cancer susceptibility genes, which are relatively
tion accounts for a large proportion of BRCA mutations, common in the general population, are expected to ac-
it may be worthwhile to initiate testing with the com- count for the majority of breast cancers [34,44,52,60].
mon BRCA2 999del5 mutation first; if negative, testing Variants in these genes may confer a modest increase
for the other BRCA mutations may be considered. In in breast cancer risk and are thought to interact with
individuals of British and Dutch ancestry, it is critical both exogenous (diet and pollution) as well as endoge-
to include rearrangement studies to evaluate for the re- nous (hormonal) risk factors [52,54]. Numerous low-
current exon 13 duplication in the British population penetrance genes have been identified including en-
and the large deletions of exon 13 and 22 in the Dutch zymes involved in DNA repair, cell signaling process-
population; these rearrangements cannot be detected es, detoxification of reactive oxygen species, as well as
by full gene sequence analysis alone. For individuals metabolism of estrogen, carcinogens, and alcohol [21].
presenting with breast cancer who are of Ashkenazi These genes have almost exclusively been studied in
Jewish ancestry it is recommended to start genetic test- Caucasian populations and limited information is avail-
ing with evaluation for the three founder mutations. If able on whether these low-penetrance genes contribute
the family is of high risk (i.e., highly suspicious for to increased cancer risks in other populations. Al-
a BRCA mutation such as a history of multiple cases though some laboratories have recently started offering
of breast and/or ovarian cancer), complete analysis of clinical testing for some of these low-penetrance genes,
BRCA genes may be warranted. For such families it clinical management based on test results of these genes
is worthwhile to continue with further genetic testing remains controversial. In addition, many of these tests
to increase the negative predictive value of the test, as were developed for other genetic syndromes and were
J. Culver et al. / Assessing Breast Cancer Risk and BRCA1/2 Carrier Probability 17

not initially intended to screen for breast cancer risk referral patterns. In general, the guidelines recommend
(i.e. ATM gene testing was originally developed for di- referral for cancer genetics services for early onset
agnostic testing for ataxia-telangiectasia or CDKN2A breast cancer or diagnosis of any age of ovarian cancer
(p16) gene testing was originally developed for heredi- and/or a family history concerning for hereditary beast
tary melanoma). In addition, some commercial labora- ovarian cancer syndrome. The guidelines also take into
tories (for example, a lab called Oncovue) have begun account non-BRCA genes, which can cause hereditary
offering breast cancer risk genetic testing on various breast cancer such as PTEN and p53, by including fam-
low-penetrance genes as well as variants in single nu- ily history of thyroid cancer, sarcoma, adrenocortical
cleotide polymorphisms (SNPs), however, such testing carcinoma, endometrial cancer, brain tumors, dermato-
is generally considered premature and is not typically logic manifestations or leukemia/lymphoma [20].
practiced in cancer genetics clinics. A detailed review USPSTF The United States Preventive Services Task
of low penetrance genes is presented by Nusbaum et Force published a recommendation statement for the
al. in this issue. referral of unaffected women for genetic counseling
and evaluation for BRCA testing [68]. The recommen-
dation, published with supporting scientific evidence,
CRITERIA FOR REFERRAL FOR GENETIC recommended which women without a personal history
COUNSELING AND TESTING of breast or ovarian cancer should be referred. Guide-
lines are shown in Table 6.
It is critical that individuals who are at risk for heredi- NICE The National Institute for Health and Clinical
tary cancer syndromes be identified as they may benefit Excellence (NICE) of the United Kingdom published
from increased surveillance to detect cancer at earlier guidelines to classify women at risk of familial breast
more treatable stages as well as preventative interven- cancer. NICE is an independent organization respon-
tion strategies. Due to the myriad of different published sible for providing national guidance on the promo-
diagnostic and referral criteria, it is often challenging tion of good health and the prevention and treatment
for health care providers to determine who should be re- of ill health. The NICE guidelines include primary,
ferred for genetic cancer risk assessment. Furthermore, secondary, and tertiary management for women with
there are differences in guidelines for who should be re- a family history of breast cancer. Recommendations
ferred for risk assessment versus who is appropriate for for referral to tertiary management (genetic counsel-
genetic testing. Most referral guidelines are less strin- ing) are shown in Table 6, and are more stringent than
gent than diagnostic/genetic testing guidelines, which the USPSTF guidelines. The guidelines also include
helps to ensure that all high-risk individuals are identi- recommendations for cancer surveillance in high risk
fied. individuals [42].
Below is a review of some of the published clinical Hampel Hampel et al. published risk assessment
practice guidelines for referral to cancer genetics ser- criteria designed to guide health care professionals in
vices. Table 6 also provides a summary of some of the identifying individuals who are appropriate for referral
criteria below. Additionally, in the United States, crite- to cancer genetics services [31]. Guidelines for referral
ria for genetic testing for BRCA1 and BRCA2 have been were created from review of published diagnostic cri-
established by third party payers (such as Kaiser, Medi- teria for hereditary cancer syndromes. When the pub-
care, Aetna, Blue Cross, etc.). These criteria change lished guidelines differed from each other, the authors
frequently and can be accessed directly from these in- used expert opinion to develop their guidelines. The
stitutions. goal of the criteria was to assist health care providers in
NCCN The National Comprehensive Cancer Net- recognition of individuals who would benefit from risk
work (NCCN) is a group of 20 United States cancer cen- assessment and create uniformity in referral guidelines.
ters designated by the United States National Cancer ASCO The American Society of Clinical Oncology
Institute as comprehensive cancer centers. The NCCN published a consensus statement in 1996 and an updat-
Genetic/Familial High Risk Assessment panel, which ed consensus statement in 2003 guiding when cancer
consists of experts within the field from the NCCN susceptibly genetic testing should be used. ASCO rec-
member organizations, has published guidelines for ge- ommends that genetic cancer risk assessment and ge-
netic/familial risk assessment of breast and ovarian can- netic testing be offered to individuals when 1) there is a
cer [20], shown in Table 6. The guidelines include con- personal or family history suggestive of a genetic can-
sensus statements from the panel of experts of accepted cer susceptibility syndrome 2) the genetic test can be
18 J. Culver et al. / Assessing Breast Cancer Risk and BRCA1/2 Carrier Probability

adequately interpreted 3) the results of genetic testing [4] Prevalence and penetrance of BRCA1 and BRCA2 mutations
will influence medical management. Initial guidelines in a population-based series of breast cancer cases. Anglian
Breast Cancer Study Group, Br J Cancer 83 (2000), 1301–
in 1996 suggested that a person with a 10% or greater 1308.
probability of having a mutation for hereditary cancer [5] Progeny Software, LLC. Southbend, Indiana; Copyright 2006.
syndrome should be offered genetic testing [10]. The http://www.progenysoftware.com/.
2003 guidelines were revised to reflect that for many of [6] A.C. Antoniou, F. Durocher, P. Smith et al., BRCA1 and
BRCA2 mutation predictions using the BOADICEA and
the syndromes it is difficult to accurately predict muta- BRCAPRO models and penetrance estimation in high-risk
tion probability or there is variance between the muta- French-Canadian families, Breast Cancer Res 8 (2006), R3.
tion probability models; therefore, ASCO does not rec- [7] A.C. Antoniou, P.D. Pharoah, G. McMullan et al., A compre-
ommend a numerical threshold of when genetic testing hensive model for familial breast cancer incorporating BRCA1,
BRCA2 and other genes, Br J Cancer 86 (2002), 76–83.
should be offered but instead states that expert clinical [8] A.C. Antoniou, P.P. Pharoah, P. Smith et al., The BOADICEA
judgment is more appropriate [9]. model of genetic susceptibility to breast and ovarian cancer,
NSGC The National Society for Genetic Counselors Br J Cancer 91 (2004), 1580–1590.
recommends that a referral for cancer genetic risk [9] ASCO, American Society of Clinical Oncology policy state-
ment update: Genetic testing for cancer susceptibility, J Clin
assessment and counseling should be considered for Oncol 21 (2003), 2397–2406.
clients with personal or family history features sugges- [10] ASCO, Statement of the American Society of Clinical On-
tive of familial or hereditary cancer and should not be cology: genetic testing for cancer susceptibility, Adopted on
limited to just those individuals who are potential can- February 20, 1996, J Clin Oncol 14 (1996), 1730–1736.
[11] L.H. Baker, Breast Cancer Detection Demonstration Project:
didates for genetic testing. Individuals from high-risk five-year summary report, CA Cancer J Clin 32 (1982), 194–
families may benefit from a detailed discussion about 225.
hereditability of cancer in their families, appropriate [12] D.A. Berry, E.S. Iversen, Jr., D.F. Gudbjartsson et al.,
cancer risk management strategies, and the option of BRCAPRO validation, sensitivity of genetic testing of BRCA1/
BRCA2, and prevalence of other breast cancer susceptibility
genetic testing [63]. genes, J Clin Oncol 20 (2002), 2701–2712.
In conclusion, the tools in this article will enable [13] D.A. Berry, G. Parmigiani, J. Sanchez et al., Probability of car-
health care providers to identify individuals with in- rying a mutation of breast-ovarian cancer gene BRCA1 based
creased breast cancer risk, estimate their risk, as well on family history, J Natl Cancer Inst 89 (1997), 227–238.
[14] M.L. Bondy, E.D. Lustbader, S. Halabi et al., Validation of a
as determine the probability that they may carry a breast cancer risk assessment model in women with a postive
BRCA1 or BRCA2 mutation. By finding individuals family history, J Natl Cancer Inst 86 (1994), 620–625.
with an increased risk of breast cancer, health profes- [15] P.O. Chappuis, N. Hamel, A.J. Paradis et al., Prevalence of
sionals can offer prevention strategies to reduce risk as- founder BRCA1 and BRCA2 mutations in unselected French
Canadian women with breast cancer, Clin Genet 59 (2001),
sociated with breast and ovarian cancer. Additionally, 418–423.
the published guidelines summarized above will help [16] E.B. Claus, S. Petruzella, E. Matloff et al., Prevalence of
providers make appropriate referrals to genetic services BRCA1 and BRCA2 mutations in women diagnosed with duc-
for further evaluation and genetic testing. tal carcinoma in situ, Jama 293 (2005), 964–931.
[17] E.B. Claus, N. Risch and W.D. Thompson, Autosomal domi-
nant inheritance of early-onset breast cancer: Implications for
risk prediction, Cancer 73 (1994), 643–651.
ACKNOWLEDGEMENTS [18] E.B. Claus, N. Risch and W.D. Thompson, The calculation
of breast cancer risk for women with a first degree family
history of ovarian cancer, Breast Cancer Res Treat 28 (1993),
The authors thank Wylie Burke, MD, PhD for her 115–120.
assistance in compiling the material in Tables 1 and 2, [19] F. Couch, M.L. DeShano, A. Blackwood et al., BRCA1 muta-
as well as the discussion of pedigree-based risk assess- tions in women attending clinics that evaluate the risk of breast
ment and the Claus model. cancer, N Engl J Med 336 (1997), 1409–1415.
[20] NCCN Practice Guidelines in Oncology: Genetic/familial
high-risk assessment: breast and ovarian 2006 http://www.
nccn.org/professionals/physician gls/PDF/genetics screening
REFERENCES .pdf.
[21] R.G. Dumitrescu and I. Cotarla, Understanding breast cancer
[1] BreastCa for Palm 2001 http://www.palmgear.com/index. risk – where do we stand in 2005?, J Cell Mol Med 9 (2005),
cfm?fuseaction=software.showsoftware&prodID=29820. 208–221.
[2] Gail Model Breast Cancer Risk Assessment Tool http://www. [22] D.G. Evans, D.M. Eccles, N. Rahman et al., A new scoring
cancer.gov/bcrisktool/. system for the chances of identifying a BRCA1/2 mutation out-
[3] NSABP Model 2, BeastCa for Palm 2001 http://www. performs existing models including BRCAPRO, J Med Genet
palmgear.com/index.cfm?fuseaction=software.showsoftware 41 (2004), 474–480.
&prodID=29820.
J. Culver et al. / Assessing Breast Cancer Risk and BRCA1/2 Carrier Probability 19

[23] D.G. Evans, F. Lalloo, A. Wallace et al., Update on the Manch- [41] H.C. Mefford, L. Baumbach, R.C.K. Panguluri et al., Evidence
ester Scoring System for BRCA1 and BRCA2 testing, J Med for a BRCA1 founder mutation in families of West African
Genet 42 (2005), e39. Ancestry, Am J Hum Genet 65 (1999), 575–578.
[24] D.G.R. Evans, S.L. Neuhausen, M. Bulman et al., Haplotype [42] National Institute for Health and Clinical Excellence (NICE),
and cancer risk analysis of two common mutations, BRCA1 Clinical Guideline 41: Familial breast cancer: the classifica-
4184del4 and BRCA2 2157delG, in high risk northwest Eng- tion and care of women at risk of familial breast cancer in pri-
land breast/ovarian families, J Med Genet 41 (2004), e21. mary, secondary, and tertiary care. October 2006. http://www.
[25] B. Fisher, J.P. Costantino, D.L. Wickerham et al., Tamoxifen nice.org.uk/guidance/cg41/quickrefguide/pdf/English.
for prevention of breast cancer: Report of the national surgical [43] R.L. Nussbaum, R.R. McInnes and H.F. Willard, Thompson &
adjuvant breast and bowel project P-1 study, J Natl Cancer Thompson Genetics in Medicine, 6th edn2001, Philadelphia,
Inst 90 (1998), 1371–1388. Pa: W. B. Suanders Company.
[26] D. Ford and D.F. Easton, The genetics of breast and ovarian [44] S. Oesterreich and S.A. Fuqua, Tumor suppressor genes in
cancer, Br J Cancer 72 (1995), 805–812. breast cancer, Endocr Relat Cancer 6 (1999), 405–419.
[27] T.S. Frank, A.M. Deffenbaugh, J.E. Reid et al., Clinical char- [45] O.I. Olopade, J.D. Fackenthal and G. Dunston et al., Breast
acteristics of individuals with germline mutations in BRCA1 cancer genetics in African Americans, Cancer 97 (2003),
and BRCA2: analysis of 10,000 individuals, J Clin Oncol 20 236–245.
(2002), 1480–1490. [46] J.H. Olsen, N. Seersholm, J.D. Boice, Jr. et al., Cancer risk
[28] E. Friedman, R.B.S. Bruchim, A. Kruglikova et al., Double in close relatives of women with early-onset breast cancer–a
Heterozygotes for the Ashkenazi founder mutations in BRCA1 population-based incidence study, Br J Cancer 79 (1999),
and BRCA2 genes, Am J Hum Genet 63 (1998), 1224–1227. 673–679.
[29] M.H. Gail, L.A. Brinton, D.P. Byar et al., Projecting individ- [47] G. Parmigiani, D. Berry and O. Aguilar, Determining carrier
ualized probabilities of developing breast cancer for white fe- probabilities for breast cancer-susceptibility genes BRCA1 and
males who are being examined annually, J Natl Cancer Inst BRCA2, Am J Hum Genet 62 (1998), 145–158.
81 (1989), 1879–1886. [48] T. Peelen, M. van Vliet, A. Petrij-Bosch et al., A high pro-
[30] Q. Gao, S. Neuhausen, S. Cummings et al., Recurrent Germ- portion of novel mutations in BRCA1 with strong founder ef-
Line BRCA1 Mutations in Extended African American Fam- fects among Dutch and Belgian hereditary breast and ovarian
ilies with Early-Onset Breast Cancer, Am J Hum Genet 60 cancer families, Am J Hum Genet 60 (1997), 1041–1049.
(1997), 1233–1236. [49] A. Petrij-Bosch, T. Peelen, M. van Vliet et al., BRCA1 genomic
[31] H. Hampel, K.M. Sweet, J.A. Westman et al., Referral for deletions are major founder mutations in Dutch breast cancer
cancer genetics consultation: a review and compilation of risk patients, Nat Genet 17 (1997), 341–345.
assessment criteria., J Med Genet 41 (2004), 81–91. [50] P.D. Pharoah, N.E. Day, S. Duffy et al., Family history and the
[32] E.S. Hwang, J.L. McLennan, D.H. Moore et al., Ductal car- risk of breast cancer: a systematic review and meta-analysis,
cinoma in situ in BRCA mutation carriers, J Clin Oncol 25 Int J Cancer 71 (1997), 800–809.
(2007), 642–647. [51] C.A. Poole, T. Byers, E.E. Calle et al., Influence of a family
[33] G. Johannesdottir, J. Gudmundsson, J.T. Bergthorsson et al., history of cancer within and across multiple sites on patterns of
High prevalence of the 999del5 mutation in Icelandic breast cancer mortality risk for women, Am J Epidemiol 149 (1999),
and ovarian cancer patients, Cancer Res 56 (1996), 3663– 454–462.
3665. [52] T.R. Rebbeck, Inherited genetic predisposition in breast can-
[34] M.C. Johnson-Thompson and J. Guthrie, Ongoing research cer: A population-based perspective, Cancer 86 (1999),
to identify environmental risk factors in breast carcinoma, 2493–2501.
Cancer 88 (2000), 1224–1229. [53] B.B. Roa, A.A. Boyd, K. Volcik et al., Ashkenazi Jewish
[35] N.D. Kauff, E. Brogi, L. Scheuer et al., Epithelial lesions in population frequencies for common mutations in BRCA1 and
prophylactic mastectomy specimens from women with BRCA BRCA2, Nat Genet 14 (1996), 185–187.
mutations, Cancer 97 (2003), 1601–1608. [54] N. Rothman, S. Wacholder, N.E. Caporaso et al., The use of
[36] N.D. Kauff, P. Perez-Segura, M.E. Robson et al., Incidence common genetic polymorphisms to enhance the epidemiologic
of non-founder BRCA1 and BRCA2 mutations in high risk study of environmental carcinogens, Biochim Biophys Acta
Ashkenazi breast and ovarian cancer families, J Med Genet 39 1471 (2001), C1–10.
(2002), 611–614. [55] W.S. Rubinstein, Hereditary breast cancer in Jews, Fam Can-
[37] U.S. Khoo, K.Y. Chan, A.N. Cheung et al., Recurrent BRCA1 cer 3 (2004), 249–257.
and BRCA2 germline mutations in ovarian cancer: a founder [56] H.A. Shih, F.J. Couch, K.L. Nathanson et al., BRCA1 and
mutation of BRCA1 identified in the Chinese population, Hum BRCA2 mutation frequency in women evaluated in a breast
Mutat 19 (2002), 307–308. cancer risk evaluation clinic, J Clin Oncol 20 (2002), 994–
[38] A. Liede, K. Metcalfe, K. Offit et al., A family with three 999.
germline mutations in BRCA1 and BRCA2, Clin Genet 54 [57] D. Spiegelman, G.A. Colditz, D. Hunter et al., Validation of
(1998), 215–218. the Gail et. al. model for predicting individual breast cancer
[39] K.A. McGuigan, P.A. Ganz and C. Breant, Agreement between risk, J Natl Cancer Inst 86 (1994), 600–607.
breast cancer risk estimation methods, J Natl Cancer Inst 88 [58] J. Stopfer, The development and validation paper for the Penn
(1996), 1315–1317. II model is currently under review, Personal Communication.
[40] A. McTiernan, A. Kuniyukik, Y. Yasui et al., Comparisons of [59] J.F. Stratton, P. Pharoah, S.K. Smith et al., A systematic review
Two Breast Cancer Risk Estimates in Women with a Family and meta-analysis of family history and risk of ovarian cancer,
History of Breast Cancer, Cancer Epidemiol Biomarkers Prev Br J Obstet Gynaecol 105 (1998), 493–499.
10 (2001), 333–338. [60] G.J. te Meerman and E.G. de Vries, Relevance of high and
low penetrance, Lancet 358 (2001), 331–332.
20 J. Culver et al. / Assessing Breast Cancer Risk and BRCA1/2 Carrier Probability

[61] A. Tesoriero, C. Andersen, M. Southey et al., De NovoBRCA1 Med 23 (2004), 1111–1130.


mutation in a patient with breast cancer and in inherited [68] USPSTF, Genetic risk assessment and BRCA mutation testing
BRCA2 mutation, Am J Hum Genet 65 (1999), 567–569. for breast and ovarian cancer susceptibility: recommendation
[62] P.N. Tonin, C. Perret, J.A. Lambert et al., Founder BRCA1 statement, Ann Intern Med 143 (2005), 355–361.
and BRCA2 mutations in early-onset French Canadian breast [69] R.B. van der luijt, H.A. can Zon, R.P.M. Jansen et al., De
cancer cases unselected for family history, Int J Cancer 95 novo recurrent germline mutation of the BRCA2 gene in a
(2001), 189–193. patient with early onset breast cancer, J Med Genet 38 (2001),
[63] A. Trepanier, M. Ahrens, W. McKinnon et al., Genetic Cancer 102–105.
Risk Assessment and Counseling: Recommendations of the [70] J. Weitzel, B. Hendrickson, V. Lagos et al., Identification of
National Society of Genetic Counselors, J Genet Couns 13 a Novel Frequent Large Genomic Rearrangement of BRCA1
(2004), 83–114. in High-risk Hispanic Families. In: The American Society of
[64] H. Tulinius, V. Egilsson, G.H. Olafsdottir et al., Risk of Human Genetics: 2005; Salt Lake City, Utah; 2005: A:362.
prostate, ovarian, and endometrial cancer among relatives of [71] J.N. Weitzel, C.A. Cullinane, V.I. Lagos et al., Family Struc-
women with breast cancer, Bmj 305 (1992), 855–857. ture Predicts BRCA Mutations in Single Cases of Breast Can-
[65] H. Tulinius, G.H. Olafsdottir, H. Sigvaldason et al., The effect cer, Submitted.
of a single BRCA2 mutation on cancer in Iceland, J Med Genet [72] J.N. Weitzel, V. Lagos, K.R. Blazer et al., Prevalence of BRCA
39 (2002), 457–462. mutations and founder effect in high-risk Hispanic families,
[66] H. Tulinius, G.H. Olafsdottir, H. Sigvaldason et al., Neoplastic Cancer Epidemiol Biomarkers Prev 14 (2005), 1666–1671.
diseases in families of breast cancer patients, J Med Genet 31 [73] P.A. Wingo, H.W. Ory, P.M. Layde et al., The evaluation of the
(1994), 618–621. data collection process for a multicenter, population-based,
[67] J. Tyrer, S.W. Duffy and J. Cuzick, A breast cancer prediction case-control design, Am J Epidemiol 128 (1988), 206–217.
model incorporating familial and personal risk factors, Stat

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