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Step 3: Selecting Risk Probability

Objectives

1.   Differentiate between risk probability and empiric risk

2.   Describe measures of determining risk probability as part of the genomic risk assessment

3.   State evidence-based models that can be used as empiric risk models

78Risk probability focuses on genetic risk or the probability or likelihood of an individual carrying a genetic mutation that further predisposes the individual for disease development (Baptista, 2005). Empiric risk is the chance of disease occurrence based on personal history, family history, or other important data. In the genomic risk assessment, evaluation of risk for the probability of having a genetic mutation that may predispose an individual to develop disease is as important as determination of disease risk based on noninherited disorders. Collected medical data, particularly the family history, play a key role in determining both genetic risk probability and empiric disease risk. Assessment of the family history for patterns suggestive of Mendelian inheritance may indicate the need to counsel the patient on genetic testing. A family history with a known genetic mutation may indicate a “high probability” of additional family members with the mutation based on the genetic disorder. The genetic disorder coupled with the individual’s position in the family could also warrant the need for genetic counseling and the possibility of genetic testing for the patient. Figure 7.1 presents a fictitious case with a high probability of a Mendelian genetic disease suspect for an AD inherited breast cancer syndrome like hereditary breast and ovarian cancer (HBOC) based on the family history. Of significance is a family history of multiple female members with breast cancer in first-, second-, and third-degree relatives (proband, sibling, mother, aunts, grandmother), a male with breast cancer (cousin), a member with ovarian and breast cancers (grandmother), and early age onset of disease (age 40, breast; age 40, ovarian) on the maternal lineage. In another example (Figure 7.2), there is a single case of breast cancer without a well-defined pattern of inheritance; however, the limited family structure of few females and possibility of paternal inheritance, coupled with early age of onset of breast cancer (age 40) with triple negative disease, strongly suggests a high probability of a genetic inherited breast cancer syndrome based on personal history and the presence of red flags. In the previous hemochromatosis case (Figure 5.5), the male and female siblings may warrant counseling and genetic testing for the known mutation given that each sibling has a 25% risk of developing the disease as a result of the parent’s carrier status as well as a 50% risk of himself or herself being a carrier of the disorder.

Although the history, especially that of the family, is the mainstay regarding genetic risk probability, there are prediction models to calculate genetic risk when a family history is suspect for specific inherited condition(s). BOADICEA, BRCAPRO, and CancerGene are examples of risk prediction models for the purpose of computing BRCA1 and BRCA2 mutation carrier probabilities for HBOC syndrome (Lee et al., 2014; Mazzola, Blackford, Parmigiani, & Biswas, 2015; UT Southwestern Medical Center, 2004). These models are used, if needed, with other data, especially that of family history for genetic risk prediction as noted. These models should be left to trained health care providers when applied to a clinical setting to ensure appropriate use and interpretation.

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