• 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).