Another challenge includes how to handle incidental findings — findings not anticipated based on family history — particularly of germline gene variants with potential implications in not only oncology, but for other disease states.7 The American Society of Clinical Oncology (ASCO) policy statement update about genetic and genomic testing for cancer susceptibility states that ASCO supports sharing medically relevant incidental germline findings from somatic mutation profiling of patients, and clinicians should counsel patients about the potential for incidental findings prior to testing them for somatic mutations.9 ASCO encourages clinicians to honor patient requests for results about incidental findings.

Multigene analysis also frequently identifies VUS, with an average estimate of 2.1 VUS per patient with multigene panels.10 It is likely that NGS will identify more VUS because they can evaluate genetic hot spots, a exome, or a whole genome.11 

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It is difficult to determine whether a specific amino acid change is functional, and there are no direct functional assays to determine whether an amino acid change translates into cancer susceptibilitly.12 Algorithms have been developed to predict the potential clinical effect of an amino acid change, but should not be used to guide patient management. Therefore, because the clinical utility of VUS is unclear, identification can cause false alarms and inappropriate clinical decisions or recommendations.11,12 The ASCO policy statement therefore states that ordering and interpreting results of panels with genes with uncertain clinical utility be done by clinicians with an expertise in cancer risk assessment.9 The policy statement also notes that changes in clinical management based on a VUS is usually inappropriate.

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Given the potential benefits — as well as the challenges — associated with multigene analysis, patient counseling is a critical factor. Traditional genetic counseling approaches may not be appropriate for multigene testing, but patients should be counseled about potential implications of the results of such tests.12 Oncologists should explain that identification of VUS or genes with low or moderate risk can occur, and how the presence of certain variants could affect management decisions.


There are advantages and disadvantages of utilizing single-gene and multigene testing for cancer-associated genes. Patients should be counseled appropriately, regardless of which type of testing is selected. Follow-up visits should include a discussion about test findings, implications, and the clinical significance of sequencing results.


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