Newman B, Mu H, Butler LM, Millikan RC, Moorman PG, King M. Frequency of Breast Cancer Attributable to BRCA1 in a Population-Based Series of American Women. JAMA. 1998;279(12):915–921. doi:10.1001/jama.279.12.915
From the Department of Epidemiology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill (Drs Newman, Millikan, and Moorman and Ms Butler); and the Department of Genetics and Division of Medical Genetics, Department of Medicine, University of Washington, Seattle (Drs Mu and King and Ms Butler); and the Department of Epidemiology and Public Health, Yale University, New Haven, Conn (Dr Moorman).
Context.— Previous studies of BRCA1 mutation prevalence
have been based on high-risk groups, yielding estimates that do not reflect
the experience of the general population of US patients with breast cancer.
Objective.— To determine prevalence of known disease-related mutations and other
variants in BRCA1 and how it differs by race, age
at diagnosis, and family history status in a population-based sample of white
and black patients with breast cancer unselected for family history.
Design.— Case-control study.
Setting.— A 24-county area of central and eastern North Carolina.
Participants.— Cases were women aged 20 to 74 years diagnosed as having a first invasive
breast cancer between May 1993 and June 1996. Controls were frequency matched
to cases by 5-year age range and race. The first 211 cases and 188 controls
regardless of race and the subsequent 99 cases and 108 controls of African
American ancestry are included in this report.
Main Outcome Measure.— Germline variants at any site in the coding sequence, splice junctions,
5′ untranslated region, or 3′ untranslated region of the BRCA1 gene were analyzed in cases, and selected variants
were analyzed in controls. Screening was performed using multiplex single-strand
conformation analysis, with all potential variants confirmed using genomic
Results.— Three of 211 patients with breast cancer had disease-related variants
at BRCA1, all of which were protein-truncating mutations.
After adjustment for sampling probabilities, the proportion of patients with
breast cancer with disease-related variants was 3.3% (95% confidence interval,
0%-7.2%) in white women and 0% in black women. Young age at diagnosis alone
did not predict BRCA1 carrier status in this population.
In white women, prevalence of inherited mutation was 23% for cases with family
history of ovarian cancer, 13% for cases from families with at least 4 cases
of breast cancer with or without ovarian cancer, and 33% for cases from families
with both breast and ovarian cancer and at least 4 affected relatives. Because
these results are based on few families at the highest levels of risk, confidence
intervals around these estimates are wide. An additional 5 patients had rare
missense mutations or a single amino acid deletion, the biological significance
of which is unknown. In black women, a variant in the 3′ untranslated
region was statistically significantly more common in cases than in controls.
Conclusions.— These data suggest that in the general US population, widespread screening
of BRCA1 is not warranted. In contrast, BRCA1 mutations are sufficiently frequent in families with both breast
and ovarian cancer, or at least 4 cases of breast cancer (at any age), that
genotyping might be considered. The emerging picture of BRCA1 population genetics involves complex interactions of family history,
age, and genetic ancestry, all of which should be taken into account when
considering testing or interpreting results.
COMMERCIAL availability of genetic tests for BRCA1 and BRCA2 poses a dilemma. Many professional
and advocacy groups currently recommend testing for breast cancer predisposition
in the context of research protocols.1- 3
However, when confronted by medical concerns and by the marketplace, clinicians
and consumers may find the choice to test difficult to reject. Actual frequencies
of inherited BRCA1 mutations in white and black patients
from the general population (ie, not selected for age at diagnosis or family
history) may help inform testing decisions for the general population of American
Most information about inherited genetic susceptibility to breast cancer
has come from research on high-risk families, including the basis of proof
for BRCA1's existence,4
its localization by genetic mapping,4,5
and its cloning.6 Informativeness of families
for genetic analysis is strongly influenced by family size, number of affected
relatives, vital status of relatives, and degree of relatedness among relatives
with disease. Hence, for earlier research, families with multiple cases of
breast cancer in multiple generations were needed, thus selection for families
with young ages at diagnosis occurred. Now, testing for cancer predisposition
due to inherited BRCA1 mutation is complicated by
limited information about frequency of BRCA1 mutations
in the general population. In the human BRCA1 gene,
more than 100 distinct variants have been reported.7
Of those variants that are disease related, nearly all are frameshift or nonsense
mutations leading to truncated proteins.
The purpose of this study was to assess the potential clinical and public
health significance of inherited BRCA1 mutations
in white and black women not selected for breast cancer family history or
for age at diagnosis. A series of interrelated questions are addressed: What
proportion of breast cancer cases in the general population of white and black
women carry known disease-related variants at BRCA1?
How do these frequencies differ by age at diagnosis, race, or family history?
What are the implications of these data for genetic testing?
The Carolina Breast Cancer Study (CBCS) is a population-based, case-control
study of breast cancer in women aged 20 to 74 years from a 24-county area
of central and eastern North Carolina.8 Women
with incident, primary, invasive breast cancer were identified from 26 hospitals
using a rapid ascertainment mechanism.9 Potential
comparison women, frequency matched on age and race, were identified from
the North Carolina Division of Motor Vehicles lists for those younger than
65 years and from the US Health Care Financing Administration lists for those
aged 65 to 74 years. Nurses made home visits to conduct interviews and to
draw blood. To characterize family history, probands were asked to enumerate
first-degree relatives and report history of any cancer, irrespective of site,
and age at diagnosis. For more distant relatives, only history of breast and
ovarian cancer was queried along with relationship to the proband.
Interviews for phase 1 of the study took place from May 1993 through
December 1996, with recruitment of 890 cases and 841 controls. To increase
statistical power for subgroups, younger women and black women were oversampled
using a modification of randomized recruitment.10,11
Overall response rates were 77% for cases and 68% for controls, with blood
samples obtained for more than 95% of participants. This report focuses on
the first 211 patients with breast cancer and 188 control women, regardless
of race, and the subsequent 99 cases and 108 controls of African American
ancestry. The expense of fully genotyping BRCA1 precluded
testing the entire series of cases and controls with current technology. The
project was approved by the institutional review boards of the University
of North Carolina School of Medicine and the University of Washington. In
addition, a certificate of confidentiality was obtained from the US Department
of Health and Human Services.
Using DNA extracted from peripheral blood lymphocytes, 211 cases were
screened for germline mutations in the BRCA1 coding
sequence, splice junctions and neighboring intronic regions, 5′ untranslated
region (UTR), and 3′ UTR using multiplex single-strand conformation
analysis, as described below. In addition, DNA aliquots from all cases were
hybridized to allele-specific oligonucleotide probes for 8 frequent mutations
in European populations. As a further check on sensitivity of testing, exon
11 was screened using a protein truncation test. All potential rare variants
were evaluated by direct genomic sequencing, using bands from the single-strand
conformation analysis gel, as well as original DNA, as template. To compare
frequencies of polymorphisms and rare variants of unknown clinical significance
in cases and controls, the 188 controls were genotyped by the same methods
used for that variant in cases. The number of controls differed for some analyses
because of restricted amounts of DNA.
Forty-seven primer pairs were used to amplify BRCA1 from genomic DNA using polymerase chain reaction (PCR). Most primers
were defined previously.12,13
New primers were designed for a few regions and are defined using the notation
of Table 1 in Friedman et al12: exon 5-reverse: 5′-ATG GTT TTA TAG GAA CGC
TAT G-3′; exon 6-reverse: 5′-GGT CTT ATC ACC ACG TCA TAG-3′;
exon 8-reverse: 5′-TTT GGC AAA ACT ATA AGA TAA GG-3′; exon 9-reverse:
5′-TGC ACA TAC ATC CCT GAA CC-3′; exon 10-reverse: 5′-AGG
TCC CAA ATG GTC TTC AG-3′; exon 16A-forward: 5′-AAC AGA GAC CAG
AAC TTT GTA ATT C-3′; exon 16A-reverse: 5′-TGC ATT ATA CCC AGC
AGT ATC AG-3′; exon 16B-forward: 5′-CCA TCT TCA ACC TCT GCA TTG-3′;
exon 16B-reverse: 5′-ACT CTT TCC AGA ATG TTG TTA AGT C-3′; exon
20-forward: 5′-GCC TTA AAT ATG ACG TGT CTG CTC-3′; exon 20-reverse:
5′-TGG AAT ACA GAG TGG TGG GGT G-3′; and exon 24-forward: 5′-AGT
CGA TTG ATT AGA GCC TAG-3′. Conditions for PCR amplification and single-strand
conformation analysis were as described.13
The multiplex single-strand conformation analysis scheme allowed simultaneous
analysis of several exons or several regions of exon 11 in the same lane of
an electrophoretic gel. The PCR products from the 47 primer pairs were run
in 14 gel lanes according to band size and pattern. Within each lane, bands
corresponding to different amplified products could be easily distinguished
(Table 1). If a band shift was
observed, the fragment involved was amplified again, and direct DNA sequencing
was performed in both forward and reverse strand directions. In addition,
the shifted band was cut out of the gel, suspended in distilled water, and
sequenced. Multiplex single-strand conformation analysis detected all variants
reported in the study.
The allele-specific oligonucleotides were designed for 8 mutations.
Mutations 185delAG, 4184delTCAA, 4446C→T, and 5382insC were genotyped
using primers and conditions previously described.13
For 4 other mutations, primers were designed to distinguish normal and mutant
alleles as follows: exon 5: 300 T→G - normal: 5′-CCT TCA CAG TGT
CCT TTA-3′; mutant: 5′-CCT TCA CAG GGT CCT TTA-3′; exon
5: 331(+1) G→A - normal: 5′-AAC CAA AAG GTA TAT AAT-3′; mutant:
5′-AAC CAA AAG ATA TAT AAT-3′; exon 6: 332(−11) T→G
- normal: 5′-CTC AAA CAA TTT AAT TTC-3′; mutant: 5′-CTC
AAA CAA GTT AAT TTC-3′; exon 11: 2457 C→T - normal: 5′-ATG
GCA CTC AGG AAA GTA-3′; mutant: 5′-ATG GCA CTT AGG AAA GTA-3′.
Individual dot blots in 96-well formats contained positive and negative
controls for each screened mutation. All positive dots were confirmed by directly
sequencing both the PCR product from the analysis and an independent aliquot
from the original sample. The allele-specific oligonucleotide hybridization
independently (and blindly) confirmed the 3 protein-truncating mutations observed.
The BRCA1 exon 11 was amplified and then translated
in 3 fragments using primers and methods as described.13
No additional variants were detected by protein truncation test.
Reamplified PCR product of each variant exon or region was analyzed
by automated and/or manual direct DNA sequencing of both strands using the
original single-strand conformation analysis–PCR primers. Automated
sequencing was performed with a DNA sequencer, using dye-labeled dideoxy terminator
chemistry (ABI Prism 377, Foster City, Calif: Applied Biosystems of Perkin
Elmer). Manual sequencing was conducted with the Sequenase PCR Product Sequencing
Kit (Cleveland, Ohio: United States Biochemical) following the manufacturer's
Primer pairs and conditions for genotyping at markers flanking BRCA1 were as described.12
For those CBCS cases with a disease-related BRCA1
variant, genotypes at these markers were compared with haplotypes from high-risk
families with the same variant to assess whether the mutations shared a common
Proportions and 95% confidence intervals (CIs) were computed using SAS14 and SUDAAN15 software.
Both cases and controls were sampled using known probabilities based on race
and age; weighting was incorporated in statistical analyses to produce parameter
estimates that reflect frequencies in the underlying population. Odds ratios
(ORs) and CIs were estimated by logistic regression models using PROC GENMOD
software,16 which allowed for age and race
adjustments and provided unbiased estimates through inclusion of offset terms
derived from the sampling probabilities.
Comparisons of cases and controls with respect to race, age, and family
history of breast or ovarian cancer are shown in Table 2. Cases and controls were similar in distribution of age
and race, for which they were matched. Cases were more likely than controls
to have first-degree or more distant relatives with breast or ovarian cancer
and to have multiple affected relatives. Four women reported male relatives
with breast cancer, 2 cases and 2 controls. In subsequent tables, results
are restricted to women who identified themselves as either white or black,
since numbers of women reporting other races were small.
Three of the 211 genotyped cases carried protein-truncating mutations
in BRCA1 (Table
3, Figure 1). All 3 were
white, with breast cancer diagnosis at ages 45, 52, and 53 years. An intron
5 splicing mutation, 332(−11) T→G, was observed in 2 cases (NC1
and NC2). The family of NC1 includes a sister diagnosed as having breast cancer
at age 41 years. The family of NC2 includes a niece with ovarian cancer (the
age of the niece at diagnosis and which sibling was her parent are not known).
This intron 5 mutation destroys an acceptor splice site, leading to aberrant
messenger RNA splicing and insertion of 59 nucleotides from intron 5 into
the messenger RNA. Translation stops at codon 81 of the mutant BRCA1 sequence.12 This splice mutation
was seen in a prior series of high-risk kindreds (family 8212),
as well as in 4 other high-risk families of western European ancestry.17 Genotypes of NC1, NC2, and family 82 at markers flanking BRCA1 indicate that these families share the same ancestral
chromosome 17q21 and hence probably a common origin for the mutation (Table 4). Although not closely related,
NC1 and NC2 are from the same North Carolina county, and family 82 is from
North Carolina as well.
The single nucleotide substitution in BRCA1
exon 11, 2457 C→T, is a nonsense mutation causing an immediate stop in
translation at codon 780. This mutation was observed in NC3, whose family
includes her mother with breast cancer, a sister with bilateral breast cancer
diagnosed at a young age, another sister with breast and ovarian cancer, and
a brother with bladder cancer. This mutation was found previously in an American
kindred of Dutch ancestry with 7 cases of breast cancer in 3 generations (family
713). The same mutation was subsequently seen
in 3 families in the Netherlands, 1 in Germany, and 4 in the United States.7,18 Genotypes of NC3 and family 7 at markers
flanking BRCA1 suggest a founder effect with a recent
mutation at marker D17S1322 (Table 4).
Three missense mutations and one 3–base pair deletion were observed
in 5 patients (Table 3). The consequences
of the variants for disease risk are unknown. Substitutions of histidine for
glutamine in exon 11 at codon 1200 in 1 black case (NC6) and of glycine for
arginine in exon 20 in 2 white cases (NC7, NC8) have not been reported elsewhere.
The exon 20 variant was observed once in 148 controls in the CBCS. These cases
(NC6 through NC8) reported no relatives with breast or ovarian cancer. The
substitution of methionine for isoleucine at codon 379 was observed in 1 black
case (NC5) and 1 black control from this series and was reported once elsewhere.7 One case, NC5, reported a paternal aunt with breast
cancer and a father and brother with prostate cancer. The 3–base pair
deletion in exon 11, leading to deletion of an aspartic acid, was observed
in 1 white case (NC4) in this series, who reported a paternal aunt with ovarian
cancer. This same deletion also was seen in a breast cancer patient of English
ancestry (R. A. Eeles, written communication, December 1997).
In our study area of North Carolina, prevalence of inherited disease-related BRCA1 variants was 3.3% in white cases, 0% in black cases,
and 2.6% for the population of breast cancer patients as a whole (Table 5). All estimates were adjusted for
sampling probabilities. In white women, inherited BRCA1 predisposition was responsible for 6.6% of cases with any relative
with breast or ovarian cancer and 22.8% with any relative with ovarian cancer.
As expected, inherited mutations were more frequent in high-risk families.
Again in white women, 13.4% of cases from high-risk families with either breast
or ovarian cancer and 33% of cases from high-risk families with both breast
and ovarian cancer had a BRCA1 mutation. Breast cancer
cases diagnosed before age 50 years were no more likely to have inherited BRCA1 disease-related variants than cases diagnosed after
age 50 years. Weighted mean ages at diagnosis were 51.5 years for women with
disease-related variants, 55.8 years for women with other rare missense or
in-frame deletion mutations, and 55.7 years for all other breast cancer cases.
Variants in introns 8, 16, 18, 22 and at coding nucleotides 710, 1186,
2430, 2731, 3232, 3238, 3667, 4158, 4801, and 4956 were observed in the cases.
All of these are considered polymorphisms and have assigned PM identification
numbers.7 Five of the variants (including those
in intron 8, exon 11 at nucleotides 2430, 3232, 3667, and intron 16) are inherited
as a unit because they are in linkage disequilibrium. Four novel variants
(in exons 11, 12, 16 and intron 12) were detected in black women, all of which
are silent (no amino acid change) or occur in noncoding regions (Table 6). A fifth variant in exon 3 also
was observed in 1 black case, reported previously.7
One missense mutation, 3537 A→G in exon 11, was observed at low frequency
in black cases and controls.
The single nucleotide substitution C→G at position 36 in the 3′
UTR was more common in black cases than in black controls: 18 of 86 cases
and 5 of 74 controls had genotypes CG or GG. The rarer G allele also was observed in
1 white and 1 Native American case and 1 white control. In this series of
black women, the age-adjusted OR for breast cancer and the G allele was 3.5 (95% CI, 1.2-10.0). To provide an independent test
of association, the subsequent 99 cases and 108 controls in the CBCS who identified
themselves as black were genotyped with an age-adjusted OR for breast cancer
and the G allele of 1.7 (95% CI, 0.5-6.3). Combined,
the overall, age-adjusted OR was 2.8 (95% CI, 1.3-6.2). In black women, the
weighted mean age at diagnosis was 54.5 years for women with the rare G allele and 52.5 years for those homozygous for the C allele. The 3′ UTR site is in partial linkage disequilibrium
with a variant in intron 22. The association of the intron 22 variant with
breast cancer was not statistically significant.
In white women in this North Carolina population, the prevalence of
known, disease-related BRCA1 mutations was 3.3%.
In black women in the study described herein, there were no BRCA1 mutations of the types known to be related to disease, although
such mutations have been identified in black families selected for high risk.19,20 Hence, BRCA1
mutations are rare among incident (ie, newly diagnosed) patients with breast
cancer not selected for family history or age at diagnosis. These are the
vast majority of patients encountered in a primary care setting.
The low prevalence of 1 in 30 cases attributable to BRCA1 in white patients is consistent with statistical projections
from other population-based series of the proportion of breast cancer due
to all susceptibility genes combined.21,22
Similar results were obtained in statistical analyses of families of ovarian
cancer patients, although this approach also potentially includes susceptibility
genes other than BRCA1.23,24
As expected, BRCA1 mutation prevalence in high-risk
patient series is considerably higher. The proportion of breast cancer families
attributable to inherited BRCA1 mutations was 60%
to 75% for those reporting 3 or more cases of breast or ovarian cancer,25- 27 and 45% for families
with 3 or more cases of breast cancer in absence of ovarian cancer.28 In breast cancer patients attending referral clinics
(often because of family history and/or young age at diagnosis), 11% to 16%
inherited disease-related variants.29- 32
In contrast, 7.5% of surviving breast cancer patients from western Washington
with very early onset (<35 years) were BRCA1 mutation
carriers33 and a population-based study of
incident cases of breast cancer before the age of 40 years in Australian women
found a prevalence of 3.6% (95% CI, 0.3% to 12.6%) for protein truncation
mutations in BRCA1 (J. L. Hopper, written communication,
The North Carolina population contributed 1 in-frame deletion and several
missense mutations to a class of variants whose biological meaning is unclear.
Screening large series of well-matched controls is necessary, but not sufficient,
for clarifying the role of these variants in breast cancer because the variants
are rare in both cases and controls.34 Development
of functional assays may help determine their biological activity and thereby
clarify their clinical significance.
In black women in this series, a relatively common variant in the 3′
UTR was almost 3 times more common in cases than controls, suggesting that
this putative polymorphism may confer a moderately increased risk of breast
cancer. Although located in a noncoding region, critical sequences in the
3′ UTR do influence stability of messenger RNA and therefore phenotype.35 In the future, using cultured cells from women with
the 3′ UTR variant and those with wild-type sequence, it will be possible
to test experimentally for differences in stability of the wild-type vs variant BRCA1 message.
Who is most likely to carry a BRCA1 variant
that influences disease risk? First, ovarian cancer is an important marker
of inherited risk: 23% of white patients with breast cancer who had a family
history of ovarian cancer had an inherited mutation in BRCA1. Second, families with at least 4 cases of breast or ovarian
cancer, regardless of age, frequently reflect inherited susceptibility: 13%
of cases from high-risk families with breast or ovarian cancer and 33% of
cases from high-risk families with both breast and ovarian cancer had inherited BRCA1 mutations. Because these results are based on few
families at the highest levels of risk, any fluctuation in number of families
with BRCA1 mutations would make considerable difference
in the point estimates. Evidence that prostate cancer risk also is influenced
by BRCA136- 38
suggests that it may be worthwhile to include this cancer in future definitions
of family history to identify high-risk individuals.
None of the 43 women in the CBCS whose breast cancers were diagnosed
when they were younger than age 40 years carried disease-related BRCA1 variants. A recent report of BRCA1 testing
in women from high-risk families also noted the absence of mutations among
probands younger than 30 years.32 Similarly,
the majority of younger patients with breast cancer studied in various other
series have not tested positive for BRCA1 mutations.29- 31,33 Hence,
young age at diagnosis in itself does not identify a group of breast cancer
patients likely to have inherited susceptibility at BRCA1. However, younger average age at diagnosis in family members generally
is a better predictor.31,32 This
occurs because a history of younger ages at diagnosis in family members (including
the proband) provides more information than does the age at diagnosis of the
Three previous studies of BRCA1 found higher
prevalences of disease-related variants in their very early-onset breast cancer
Differences between prevalences of BRCA1 mutations
in young patients in those populations compared with the North Carolina population
could be due to differences in allele frequencies or to sampling variability
(CIs frequently overlap). Alternatively, unrecognized selection for patients
who were not only young, but also from high-risk families, may account for
higher estimates in the other studies. Possible explanations cannot be distinguished
because the previous studies did not include older women to evaluate overall
mutation frequency in those series or the relative distribution of variants
by age. The well-established link between BRCA1 and
early-onset breast cancer frequently overlooks the fact that nearly all families
inheriting BRCA1 or BRCA2
mutations include women whose conditions were diagnosed at a wide range of
Interpretation of risk in the context of predictive genetic testing
poses clinical dilemmas. First, negative test results (ie, no detected mutation
in BRCA1 or BRCA2) can have
any of several meanings. There may be no inherited predisposition to the disease.
Alternatively, a proportion of mutations are large deletions or genomically
complex alterations that will be missed by approaches based solely on genomic
in our series of high-risk American families,12,13
mutations detectable only by analysis of complementary DNA constituted approximately
5% to 10% of BRCA1 mutations, such mutations are
far more common in Holland,41 and hence potentially
in other populations where founder effects have major influence. Also, not
all inherited breast cancer can be attributed to BRCA1
and the other susceptibility genes have not yet been identified. Hence, unless
a specific mutation has been identified in other family member(s), a negative
test result does not provide complete information. Second, positive test results
cannot yet be interpreted precisely because risk of cancer associated with
mutation (ie, penetrance) is not yet well characterized for BRCA1 and BRCA2. Resolution of the question
of risk associated with BRCA1 in the general population
awaits analysis of women at risk, not selected from high-risk families, but
for whom individual genetic information has been obtained. No such analysis
has been completed yet, although several such analyses are in progress.
In women with inherited BRCA1 disease-associated
mutations, options for preventing breast or ovarian cancer remain limited.
Minimally, more frequent clinical screening by physical breast examination
is recommended. The benefits of mammographic screening in the general population
of women younger than 50 years remains controversial,43,44
but what about its usefulness in a high-risk population? Since the sensitivity
of mammography differs among women,45 it seems
most prudent to decide when to begin mammographic screening on an individualized
basis. Prophylactic mastectomy and oophorectomy are clearly far more drastic
alternatives, for which some data on effectiveness have recently appeared.
In women electing prophylactic mastectomy (primarily due to family history
or to prior nonmalignant breast conditions), the reduction in breast cancer
was 90% of that expected over the succeeding 17 years.46
Alternatives for women with inherited mutations that fall between the extremes
of screening and surgery, such as preventive use of tamoxifen, are under investigation.47
What should the policy for predictive genetic testing be? The social
and legal issues surrounding genetic testing remain more challenging than
the technical ones.48- 53
However, the ongoing debate may become moot as genetic testing becomes increasingly
integrated in clinical practice. Potential clinical benefits of genetic testing
may be optimized under certain conditions. Testing women from the general
population for the entire BRCA1 and BRCA2 sequences is of questionable value, because a large number of
women would be tested, expensively, to detect few mutations, and the negative
results cannot be definitive, except in the context of a family with a known
disease-related mutation. For populations with relatively common founder mutations,
selected screening of breast and ovarian cancer patients may be reasonable.
For other American women, the guidelines suggested by the results of this
study may be realistic: family history of both breast and ovarian cancer or
4 or more cases of breast cancer (at any age) in the family. In either event,
clinical decision making is substantially benefited by the involvement of
specialists familiar with the subtleties and uncertainties of genetic testing,
including how to communicate effectively results that may be inconclusive.
Coverage for medical follow-up for women with BRCA1 or BRCA2 mutations is an integral part of
any rational health care system. Currently, these costs are spread across
the entire population, usually in association with treatment of end-stage
disease. However, when possible, consequences of these predispositions will
be best treated with preventive care. Shifting the financial burden to individuals
as this becomes a prospect seems shortsighted. In the end, we all are predisposed
to some condition(s) as the consequence of our genotypes, albeit most of the
predisposing genes have not yet been identified.
In summary, prevalences of BRCA1 mutations
among breast cancer patients in this population-based study (3.3% in white
and 0% in black cases) may be generalizable to large portions of the United
States. In North Carolina, most white residents trace their ancestry primarily
to northern and western Europe (US Census Bureau data, unpublished findings,
1990). Less than 2% of North Carolina residents are of Jewish ancestry.54 Because there are few mutation carriers in this North
Carolina population, fluctuations in this number could make considerable difference
in the point estimate. However, the upper limit of the CI for white patients
(7.2%) excludes the higher estimates of prevalence observed in other studies
from clinical settings (11%-16%).29- 32
This suggests, for most of the United States, that widespread screening of
breast cancer patients (or the general population) for BRCA1 is not warranted.