Sema4 Signal® Hereditary Cancer

Sema4 Signal Variant of Uncertain Significance (VUS)
Resolution Program


A Variant of Uncertain Significance (VUS) is a genetic change for which there is currently insufficient information to determine whether it is associated with increased cancer risk. Follow-up testing of specific relatives of an individual with a VUS can sometimes clarify the clinical significance of a VUS. The Sema4 Signal VUS Resolution Program provides such testing. Although participation in this program might not result in the VUS’ immediate reclassification, reclassification may still occur as additional information becomes available. If the VUS is reclassified, the ordering provider(s) of the patient and of each family member who had follow-up testing will be notified.


Eligibility and requirements:

Applications for the Sema4 Signal VUS Resolution Program are assessed by Sema4 on a case-by-case basis. In general, genes with strong disease associations, high penetrance, and autosomal dominant inheritance are more likely to be selected. The variant itself, as well as family history factors, may also impact eligibility. Please note that not all variants can be resolved through this program.

Sema4 will determine which family members may be informative for follow-up testing and will perform this testing at no additional charge.


Sema4 Signal VUS Resolution Program application process:

Please submit the following information to

  • Completed application form – download here
  • Additional documents such as a detailed three-generation pedigree and clinical records regarding the proband’s personal and family history
  • Upon review, Sema4 may request additional information to determine eligibility and identify family members appropriate for follow-up testing.
  • An official test order (using a Sema4 test requisition form as well as informed consent) is required for each family member who is eligible for follow-up testing.


Review of the application may take up to a week. Once accepted for the family studies program, please allow 10-14 days following sample receipt for testing and reporting.

Please note, it is not guaranteed that participation in this study will lead to VUS reclassification.


If you have any questions:

Please contact us at or call the Sema4 Genetic Counseling hotline at 1-800-298-6470 option 2

Sema4 also offers targeted genetic testing for known familial pathogenic variants. For information on family variant testing at Sema4, please visit