The Option of Genetic Testing
Figure 2. This genetic testing algorithm depicts the multistep process of testing for cancer susceptibility.
Value of testing an affected family member first
Genetic susceptibility testing generally yields the most useful information when a living family member affected with the cancer of concern is tested first to determine whether a genetic basis for the cancer diagnosis can be established. Three possible outcomes for this form of testing include the following (see Figure 2):
- Deleterious mutation detected.
- No mutation detected.
- Variant of uncertain significance detected.
If a mutation that is documented to be deleterious (associated with cancer risk) is identified, risks are based on penetrance data for mutations of that specific gene. In addition, other family members may be tested for the presence or absence of this specific mutation. If no mutation is found in an affected family member, testing is considered uninformative and thus there is no basis for testing unaffected relatives. Failure of the laboratory to detect a mutation in an affected family member does not rule out an inherited basis for the cancer in that family. Reasons why testing could be uninformative include the following:
- The cancer in the family may be associated with a cancer susceptibility gene other than the gene that was tested.
- The cancer in the family may be associated with a gene mutation but the cancer in the specific family member who underwent testing is not associated with that mutation. This can occur especially with cancers that are common in the general population such as breast cancer or prostate cancer. The family member who is affected with the disease but is not a carrier of the mutated gene associated with the inherited predisposition to cancer in the family is considered a phenocopy.
- Identifying a gene mutation may not be possible given the limited sensitivity of the laboratory techniques used to detect mutations. There may be additional testing available to detect certain types of mutations that would have been missed by the initial genetic test.
- The function of the gene could be altered by a mutation in a different gene.
Lastly, testing may reveal a variant of uncertain significance. This result means that a gene mutation has been found, however, the extent that this mutation increases cancer risk, or whether it is associated with the history of cancer in the family, is uncertain. In this circumstance, some clues as to the significance of the mutation can be derived from the following:
- The location of the mutation in relation to regions and function of a gene.
- The specific change; since many variants are missense mutations, not all amino acid substitutions are as significant.
- Whether the variant has been documented in the presence of a documented deleterious mutation.
- Whether the mutation is associated with the branch in the family with the cancer and/or whether the variant tracks with the cancers in the family.