This service is available at no additional charge to patients tested at Blueprint Genetics and found to have a variant of uncertain significance (VUS) that could potentially be reclassified to likely pathogenic with informative family member testing.Please note that the purpose of the VUS clarification service is to attempt to make a diagnosis in the index patient, therefore, family members participating in this service will not receive information about their variant status. Reports are available for family members through our routine Familial Variant Testing service.
What is needed from family members participating in the VUS Clarification Service?
Effective May 10, 2022, we require a signed consent form from all family members participating in the VUS Clarification Service to ensure that they are fully aware of the purpose of the testing and how to participate. Before we can begin testing, a signed copy of the Family Member Consent Form needs to be received in our laboratory.
All samples and signed consent forms from family members must be received within 6 months from acceptance into the VUS Clarification Service (date of report for the index patient OR the date you are notified that your VUS Clarification Service application was accepted).
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.
Any VUS reported in the main findings section will fall into one of the following three categories:
1. Automatically approved
VUSs with the highest likelihood of reclassification will be automatically approved for Familial Variant 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 does not include a comment about the VUS Clarification Service, family members can be tested as part of our Familial Variant Testing service at our regular fee. For a VUS identified from whole exome sequencing, our Re-evaluation Service may be an option.
How do I complete a VUS Clarification Service application?
Please include the following information:
- Blueprint Genetics Order ID of the index patient.
- The VUS in question (cDNA sequence change or protein alteration).
- 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.
- 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. The samples and signed consent forms should be sent within 6 months after the application has been accepted.
Testing only begins once all required samples and consent forms are received in our laboratory and results take up to 4 weeks. Once the testing is completed, you will receive an updated version of the index patient report.
Send applications and supporting documents to us via land mail or fax at:
200 Forest Street
Marlborough, MA 01752
Phone: 1(650) 452-9340 Ext. 0
Fax: 1(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. If the application is accepted, instructions will include which family members are required for testing.
Will I need to provide signed consent forms for the VUS Clarification Service?
Yes, we require a signed consent form specific to our VUS Clarification Service from all participating family members before we can begin testing. Please download the form here. You can attach the signed form to the order in Nucleus, or send it to us by fax or secured email. All signed consent forms from family members must be received within 6 months from acceptance into the VUS Clarification Service (date of report for the index patient OR the date you are notified that your VUS Clarification Service application was accepted).
How will I get results once the testing is completed?
The index patient’s report will be updated to indicate whether the variant(s) have been reclassified. Please note the purpose of the VUS clarification service is to attempt to make a diagnosis in the index patient, therefore, family members participating in this service will not receive an individual report or be provided with their variant status.
- 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 (by examination and/or investigation) and unaffected (by examination and/or investigation) 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:
- 2 additional affected family members and 2 unaffected family members are available and willing to provide samples
- The phenotype of the affected family members 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 1 additional affected family member and at least 1 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 1 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). Both the VUS and LP/P variants will be analyzed in the parental samples and reported on their respective clinical statements
- If the VUS is homozygous, at least 1 additional affected sibling is required. Healthy siblings may also be required.
- The index patient was not originally tested at Blueprint Genetics
- The Clinical Statement does not contain information about the VUSClarification Service
- Only 1 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
- 2 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.
Please review the eligibility criteria and download, complete and submit the application form if your patient meets eligibility criteria. 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, Familial Variant 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 Familial Variant Testing.
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 Familial Variant 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.
Based on the information provided to the laboratory and/or the variant characteristics, these variants are not thought to be the likely cause for the patient’s phenotype. Therefore, Familial Variant Testing does not provide additional information helpful for the reclassification.
In this service, our focus is to help patients find an explanation for the disease. However, Familial Variant Testing can always be used for testing of variants that a more likely to be reclassified likely benign (at a regular price).