A classification of variant of uncertain significance (VUS) is assigned if there is insufficient information about the variant to lead to a benign, likely benign, pathogenic, or likely pathogenic interpretation. Because the clinical significance of a VUS is unknown, these test results generally cannot be used for risk assessment or medical management purposes.
In some situations, testing family members for the presence or absence of a VUS may provide information that could contribute to the eventual reclassification of a VUS to a clinically meaningful result. Family members accepted into a GeneDx Variant Testing Program are offered targeted testing for the VUS at no additional charge, provided they submit all relevant clinical and/or family history information. GeneDx has sole discretion to make the final determinations for VTP participation. There is no guarantee that participation in a Variant Testing Program will lead to reclassification of a VUS.
Laboratories classify genetic changes as variants of uncertain significance (VUS) if there is incomplete or conflicting information about the health consequences of the variant. In some cases, testing family members for the presence or absence of the VUS may contribute to a better understanding of the variant and may be one piece of evidence leading to eventual reclassification of a VUS as a pathogenic, likely pathogenic, benign, or likely benign variant. For such cases, GeneDx has established a Variant Testing Program (VTP).
GeneDx considers requests for the VTP for any individual found to have a VUS identified through genetic testing at our laboratory. Targeted variant testing for the variant(/s) will be performed at no additional charge for select and pre-approved family members who meet certain criteria and for whom appropriate clinical information is provided. Genetic testing for other variants or additional family members, including predictive testing, is not included in our VTP and can be ordered separately for charge. GeneDx will make the final determinations regarding inclusion in our VTP at its sole discretion.
In some cases, the ‘Recommendations’ section of the proband’s report may specify that testing for a variant is available at no additional charge through the VTP for the biological mother and biological father of the proband. Clinical information on the parents (and proband) must be provided at the time of testing in order for targeted testing to be performed at no charge, but no additional prior approval is required for these cases.
If parents are not available, there may be other informative family members eligible for VTP testing. Requests to consider testing for relatives other than the biological parents, or requests for other variants not specified in the ‘Recommendations’ section of the report, should be submitted for advance review. Please email a detailed pedigree and any relevant clinical information/evaluations to the GeneDx genetic counselors at firstname.lastname@example.org, or call 301-519-2100 and ask to speak with a genetic counselor. Please be sure to indicate that you are submitting the information for VTP consideration and include the name and/or GeneDx accession number of the proband.
Our team will review the case and will determine if there are informative family members appropriate for evaluation through the VTP. Cases are typically reviewed within a few days.
A member of our team will contact the ordering provider or genetic counselor after the case has been reviewed to let them know if the family has been accepted in the VTP. If we are extending an offer for family member variant testing at no additional charge, we will discuss logistics of specimen submission at that time.
There are no informative family members available for testing.
In certain circumstances, it may be more informative to perform more comprehensive diagnostic genetic testing in affected family member(s) instead of targeted testing of one or more unaffected relatives for a VUS.
The variant is in a gene that does not correspond well with the clinical phenotype reported in the proband or the medical history in the family.
Segregation studies involving genes with incomplete penetrance or variable age-of-onset are challenging, especially in unaffected individuals; therefore, VTP studies are less likely to be approved for such genes.
Variant studies for the evaluation of a single VUS in a gene associated with an autosomal recessive disorder are rarely informative. Therefore, these requests are typically denied.
The VUS is present in the mosaic state.
Revising the classification of variants of uncertain significance generally requires a great deal of data and information from multiple sources. Therefore, there is no guarantee that participation in the VTP will lead to an updated classification of a VUS based on information from a single family, although cumulative data collected from multiple families over time may lead to a more definitive classification for a variant.