VUS Clarification Service

This free-of charge service is available to patients tested at Blueprint Genetics and found to have a variant of uncertain significance (VUS) that could potentially be reclassified to likely pathogenic on the basis of family member testing.

How do I know if my patient is eligible for this service?

Our team of geneticists will automatically assess any VUS reported in the main findings section of the Clinical Statement for VUS Clarification Service eligibility. If family member testing is likely to result in the reclassification of the VUS, the reporting geneticist will note this in the Conclusion section of the index patient’s Clinical Statement. VUS Clarification Service eligibility will be included in Clinical Statements reported on or after Nov 12th, 2018.

Any VUS reported in the main findings section on or after November 12, 2018 will fall into one of the following three categories:

1. Automatically approved

VUSs with the highest likelihood of reclassification will be automatically approved for family member testing as part of the VUS Clarification Service (for example, testing unaffected parents to determine phase of the VUS and likely pathogenic/pathogenic variant or whether a variant is de novo). Please refer to the Conclusion section of the patient’s Clinical Statement for further instructions.

2. Additional information needed; application suggested

If there is a possibility the VUSs might be reclassified depending on the family history, family structure and availability of family members to provide sample, the Conclusion section of the Clinical Statement will suggest that you submit an application to the VUS Clarification Service (instructions below).

3. Not eligible for the VUS Clarification Service

If your patient’s report was issued after November 12, 2018 and does not include a comment about the VUS Clarification Service, free-of-charge family member testing is not available. However, family members can be tested as part of our Family Member Testing service at our regular fee. For VUS identified from whole exome sequencing, our Re-evaluation Service may be an option.

Family member testing takes approximately 3-4 weeks.

Note: If your patient’s results were reported before November 12, 2018, please review the eligibility criteria below and download, complete and submit the application form if your patient meets eligibility criteria.

How do I complete a VUS Clarification Service application?

Please include the following information:

  1. Blueprint Genetics Order ID of the index patient.
  2. The VUS in question (cDNA sequence change or protein alteration).
  3. A detailed family history including the number of affected and unaffected family members in each generation and a description of the phenotypes of all affected family members.
  4. Which family members, affected and unaffected, are available for testing and willing to provide samples.

Please do not send samples before the application is reviewed and a decision is made.

After receiving the completed application, our interpretation team reviews the information to determine if family member testing is likely to result in reclassification of the VUS to likely pathogenic or pathogenic and, if yes, which family members need to provide samples. You will receive the decision by email in 3-4 weeks. Testing only begins once all required samples are received in our laboratory. The samples should be sent within 6 months after the application has been accepted.

If the VUS is re-classified, an updated report will be issued for all individuals who previously tested positive for this variant. If the VUS is not re-classified, all family members who participated in testing will receive a report indicating whether or not they carry the VUS.

 

Download the application form

Send applications and supporting documents to us via land mail or fax at:

Support:

Blueprint Genetics
1268 Missouri Street
San Francisco
CA 94107
USA

Phone: (650) 452-9340 Ext. 0
Fax: (650) 446-7790

If you need further assistance, please contact our Clinical Genetics Support team.

Blueprint Genetics will contact the healthcare provider to advise them of the decision and provide them with instructions and what samples are required if the application is accepted.

  • There is a strong association between the gene and patient’s phenotype
  • The gene is well-established as a disease-causing gene
  • The inheritance pattern makes sense given the disease and the gene
  • There are sufficient affected and unaffected family members to confidently demonstrate segregation, their phenotypes are well-documented and the family members are willing to provide samples for testing
  • The VUS was identified by single gene, panel or exome testing performed at Blueprint Genetics

An autosomal dominant condition with a positive family history:

  • Two additional affected family members and two unaffected family members are available and willing to provide samples
  • The phenotype of the affected individuals is well-documented and their symptoms are consistent with the condition/phenotype described in the index case

An autosomal dominant condition with a negative family history:

  • If the index patient has a syndrome or disorder that is expected to be caused by a de novo variant, testing of both parents may be sufficient to reclassify the variant

An X-linked condition with a positive family history:

  • At least one additional affected family member and at least one unaffected male family member are available and willing to provide samples
  • The phenotype of the affected individuals is well-documented and their symptoms are consistent with the condition/phenotype described in the index case

An X-linked condition with a negative family history:

  • If the index patient has a syndrome or disorder that is expected to be caused by a de novo mutation, testing the mother (or both parents if the index patient is female) may be sufficient to reclassify the variant
  • Additional maternally related male relatives may be required

An autosomal recessive condition:

  • If one pathogenic or likely pathogenic variant is identified with a VUS in the same gene, testing of both parents can be considered to clarify whether these variants are in the same allele (in cis) or in different alleles (in trans)
  • If the VUS is homozygous, at least one additional affected sibling is required.  Healthy siblings may also be required.
  • The index patient was not originally tested at Blueprint Genetics
  • The VUS was reported after November 12, 2018 and the Clinical Statement does not contain information about the VUS Clarification Service
  • Only one family member is available (this typically does not provide sufficient segregation information).  Exceptions include:
      • 1) demonstrating compound heterozygosity of a VUS and LP/P variant that are both very rare in gnomAD
      • 2) X-linked dominant disorders where a male is severely affected and has a very strong candidate VUS (testing of mother only)
  • The VUS is in a gene associated with late-onset disease and family members have not been evaluated clinically or are too young to have developed symptoms/features of the disease
  • The VUS is reported as an Additional Finding (variants reported in the additional findings section are determined by our interpretation team not to explain the patient’s phenotype based on clinical history provided)
  • The candidate genes in WES results
  • The VUS is in a gene for which the disease-gene association has limited evidence
  • Two VUSs in a gene associated with autosomal recessive disorder/disease (NB with the exception of a homozygous VUS)
  • A VUS that is likely to be reclassified to likely benign or benign.

If your patient’s report was issued prior to November 12, 2018, please review the eligibility criteria and download, complete and submit the application form if your patient meets eligibility criteria.

If your patient’s Clinical Statement was reported on or after Nov 12th, 2018, and the Clinical Statement contains a recommendation to apply to this service, please consider submitting one.

Testing of family members can determine the phase of a VUS and LP/P variant, determine whether a variant is de novo or inherited or can demonstrate segregation with the disease phenotype.  However, family member testing alone may not be sufficient for variant reclassification. Click here to see our variant classification criteria.

Our interpretation team does a thorough review of each variant in addition to the family structure and clinical information provided to determine which variants are most likely to result in a reclassification. For this reason, please allow up to 4 weeks for our decision.

To assist our interpretation team in providing you with a timely response, please ensure your application is as thorough as possible.  Do not hesitate to include supporting literature with your application.

If you require urgent testing, we recommend you use our Family Member Testing Service.

Once the application is reviewed by our interpretation team and a decision has been made, Blueprint Genetics will email the healthcare provider who submitted the application to advise them of the decision and provide them with further instructions. If the application is accepted, instructions will include which family members are required for testing.

For variants with a classification of pathogenic, likely pathogenic, likely benign, benign or for VUSs reported in the Additional Finding section of our Clinical Statement, we offer targeted variant testing through our Family Member Testing.

If the same variant is seen in another patient (related or unrelated) and results in a reclassification of the variant, we update the classification of all patients with that variant and issue a new Clinical Statement to the ordering healthcare provider.

These variants are not thought to be the likely cause for the patient’s phenotype. Therefore, Family Member Testing does not provide any information helpful for the reclassification.

In this service, our focus is to help patients find an explanation for the disease. However, Family Member testing can always be used for testing of variants that a more likely to be reclassified likely benign (at a regular price).

Last modified: 11.12.2018