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Mathematical Modeling for Breast Cancer Risk Assessment

Mathematical Modeling for Breast Cancer Risk Assessment

Rubinstein and colleagues provide an excellent review of mathematical models
for estimating breast cancer risk, including the risk of carrying inherited
mutations of BRCA1 and BRCA2. Since we and others reviewed early models to
predict the likelihood of inherited susceptibility to breast cancer,[1] newer
quantitative tools, most notably by Parmigiani and colleagues,[2] have been
developed. These models have been made available on CD-ROM, over the Internet,
and in other electronic versions that are accessible to most clinicians and
researchers. These quantitative resources constitute useful and important aids
in genetic counseling.

With this commentary, I will provide additional perspective to the excellent
overview presented by Rubinstein et al, addressing several areas that the
authors did not fully touch upon. These topics include (1) the importance of
being aware of genetic testing guidelines propagated by insurers, (2) the
probability of detecting missense variants of unknown significance as a result
of genetic testing, (3) the psychological implications of testing unaffected
probands, and (4) special aspects of testing individuals of Ashkenazi ancestry.

Finally, I will review a general caution that affects all quantitative
modeling for hereditary breast cancer. This relates to the highly selected (ie,
biased) nature of the ascertainments that have been used to generate risk
(penetrance) information.

Quantitative Estimates and Insurance Reimbursement

Perhaps the most clinically relevant application of quantitative risk
estimates relates to the use of quantitative models by third-party carriers. In
contrast to the early dire forecasts regarding insurance abuse of genetic
information, several large carriers include BRCA testing in their coverage plans
(without penalty) if specific family history criteria are met. For example, Blue
Cross/Blue Shield has issued centralized guidelines on BRCA testing.[3] However,
Blue Cross guidelines vary according to the policies of local plans in each

As part of an American Medical Association conference, the Kaiser system
circulated proposed criteria for BRCA testing,[4] and guidelines have also been
issued by Aetna/US Healthcare.[5] These policies may be of as much interest to
health-care providers as the theoretical models presented in this excellent
review. Citation of the theoretical models may be useful for clinicians seeking
to obtain insurance coverage for testing services provided to those insured by
companies without established policies.

Detecting Missense Mutations of Unknown Significance


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