VUS Clarification Service
Blueprint Genetics is dedicated to advancing and improving the field of genetic diagnostics. We offer a Variant of Uncertain Significance (VUS) Clarification Service free of charge when testing of selected additional family members is likely to clarify the disease – variant association.
The goal of the service is to gain enough additional evidence to enable re-classification of the VUS to either likely benign/benign or likely pathogenic/pathogenic. Since not all family members provide sufficient evidence for reclassification, some VUS variants or cases will not qualify for this service.
If the variant is re-classified, an amended report will be issued for all individuals who previously tested positive for this variant. We will also update our interpretation and classification in public databases such as ClinVar ultimately helping other patients and families who have also tested positive for the identified variant.
Who qualifies for the service?
Not all variants and cases qualify for the VUS Clarification service. First, Blueprint Genetics must identify the VUS in the index patient. Additionally, the following characteristics will influence qualification for this service:
- Positive family history (autosomal dominant disorder):
- Influencing factors include the number of affected family members (at least 3) and the clinical presentation of individuals in the family.
- Typically, two additional affected family members and two unaffected family members, who are biologically related to the index patient (not spouses), are required to be able to assess co-segregation of the variant with the phenotype in the family.
- Negative family history:
- Autosomal dominant, X-linked: Typically, in cases where the index patient has a syndrome or disorder that is mainly caused by a de novo mutation, testing of parents only can be considered.
- Autosomal recessive disorders: If one pathogenic or likely pathogenic variant is identified with a VUS in the same gene, testing of both variants in both parents can be considered to clarify whether these variants are in the same allele (in cis) or in different alleles (in trans).
- In all cases, a strong association between the gene and patient’s phenotype is required.
- Qualifying genes are typically well-established disease genes and harbor known variants that can be confidently classified as pathogenic.
- Affected family members have documented clinical symptoms, diagnoses, or test results consistent with the condition/phenotype described in the index case.
Mode of inheritance:
- The inheritance pattern is logical in the context of disease, gene, and the suggested testing strategy.
Who/which variants do not qualify for the VUS clarification service?
- The index patient was not originally tested at Blueprint Genetics. Please see our Family Member Testing for these cases.
- Only one family member is available. Testing of one family member generally does not provide enough evidence to qualify for the service. The two exceptions are 1) demonstrating compound heterozygosity of a VUS and LP/P variants that are both very rare in gnomAD. In this case, testing one child of the index patient is sufficient provided the parents are not consanguineous. 2) X-linked dominant disorder where male is severely affected and has very strong candidate VUS and it should be tested only from the mother.
- When the VUS is identified in a gene associated with late-onset disease, individuals who have not been clinically evaluated or individuals who are too young to have presented with the disease phenotype are not considered helpful for re-classification.
- Variants reported as additional findings (does not explain the patient’s phenotype).
- Variants in genes of uncertain significance.
- Two variants of uncertain significance in a gene associated with autosomal recessive disorder/disease.
- Any variant of uncertain significance, which could not be re-classified using suggested testing approach.
How do I apply?
Download the application form. The following information is required:
- Blueprint Genetics ID of the original patient (index) tested at Blueprint Genetics.
- The VUS in question.
- Detailed family history and the description of clinical phenotypes of all affected family members (see above criteria recommendations).
- Which family members are available for testing as part of the reclassification process.
Send applications and supporting documents to us via land mail or fax at:
US, Canada and South America
Europe, Middle East, Asia and Australia
Biomedicum Helsinki 1
|+1 650 446 7790||+358 9 8565 7177|
If you contact our customer support via email, please do not include any medical records or medical information with your initial inquiry.
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.
When should I use the Family Member Testing?
For variants with a classification of pathogenic, likely pathogenic, likely benign, or benign we offer targeted variant sequencing and analysis through our Family Member Testing. This service is also available to families who have a genetic testing result from another laboratory. If testing was previously performed at another facility, we ask that a sample from the index patient and a copy of the index patient’s report be provided for quality assurance purposes.