Table 1. Clinical Utility of Genetic/Genomic Testsa continued...
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.
Unfortunately, even with this information, there is often insufficient evidence to document the significance of a specific variant, and further clarifying research is required.
If there is no close, living, affected relative to undergo testing, or the living affected relative declines testing, other options may be discussed with the patient and the testing laboratory. These generally involve weighing the availability and reliability of testing the stored tissue of a deceased relative or testing an unaffected person without prior testing of an affected family member. Tests done on stored tissue are technically difficult and may not yield a definitive result. Testing an unaffected person without prior testing of an affected relative often is uninformative because a negative test does not rule out the presence of a cancer susceptibility gene in the family or the subject.
Testing in families with a documented deleterious mutation
Genetic susceptibility testing for a documented deleterious mutation in the family can be very informative and will yield one of the following two results (see Figure 2):
- Positive for the familial mutation.
- Negative for the familial mutation.
If the familial mutation is detected in a family member, their cancer risks are based on penetrance data for mutations in that specific gene. If the documented mutation is not found in a family member, the risk of cancer in that individual is equivalent to cancer risk in the general population. However, other risk factors and family history from the side of the family not associated with the documented mutation may increase the cancer risk above the general population levels.