Appearance
14. ClinVar Reanalysis
A genetic diagnosis depends on the evidence available at the time a case is analyzed — and that evidence changes as new gene and variant interpretations are published. Reanalyzing every past case by hand each time the evidence changes is impractical at scale. Mosaic's ClinVar reanalysis automates this: when a new ClinVar version is released, Mosaic identifies the cases where the new evidence is relevant and prompts the team to review them.
14.1. The ClinVar reanalysis methodology
The ClinVar reanalysis process is used to identify proband variants with new P/LP (pathogenic / likely pathogenic) variants, or variants that have been upgraded to P/LP from a previously B/LB (benign / likely benign) or uncertain assertion. The following sections describe how the ClinVar reanalysis process works, which variants will be identified, how the variants can be found and reviewed, and how to be notified when updates are found. Variants are assigned to one of three categories:
Primary Variants: New or upgraded P/LP variants present in the proband and present in a gene that is associated with an HPO term assigned to the proband.
Actionable Variants: New or upgraded P/LP variants present in the proband, not in an HPO-associated gene, but in one of the ACMG secondary findings genes.
Other Variants: New or upgraded P/LP variants present in the proband that are neither HPO-associated nor in an ACMG gene. These are variants that could be useful in gene discovery.
All variants will be available within the Mosaic project, but notifications will only be sent for primary variants. The rationale is that users do not wish to be burdened with too many variants, so the primary variants are an attempt to notify users only of variants with the highest likelihood of being of utility.
14.2. How many variants will be identified with each update?
Users typically have hundreds or thousands of individual cases and do not have time to review hundreds of highlighted variants every week. By applying allele frequency and HPO filters, the number of primary variants returned per genome per update is very low — typically zero. This ensures that the burden of review is kept low. These filters can always be modified to alter the balance between returning the smallest number of variants and returning all variants with any potential to be of interest.
Tip: If reanalysis is surfacing too many or too few variants for your group, the customizable criteria (such as the allele-frequency threshold and the phenotype requirement) can be tuned. Contact the Frameshift team to adjust the balance for your cohort.
14.3. How to receive notifications of variants to review
When the ClinVar review process is set up for specific cases (typically for collections), a set of email addresses is associated with the process. When variants for review have been identified, an email is sent to this list to inform them of these updates. Additionally, users should subscribe to projects or collections to receive notifications in Mosaic when variants for review are identified. To subscribe to a collection (and receive updates on all projects within the collection), go to Settings & More > Settings and then select Subscriptions from User Collection Settings and toggle on the Project Tasks subscription. Clicking on Tasks in the menu bar will, by default, show tasks for projects that you are subscribed to (see Tasks for more information).
There are two complementary notification channels: an email to the addresses associated with the reanalysis process, and in-app tasks for users who have subscribed. Subscribing to the collection means you will be notified about every project within it without subscribing to each one individually.
14.4. How to review the identified variants
ClinVar variants for review can be accessed in two primary ways.
From the Tasks menu: If there are variants to review, they can be found from the menu bar via the Tasks option. By default, clicking on Tasks in the menu bar will show you all outstanding tasks in projects you are subscribed to (see Section 14.3 above). You can click on All Projects to see all outstanding tasks in all projects. You can limit the view to ClinVar tasks by selecting Review Variants from the Task Category menu. The Status menu allows you to toggle between completed and pending tasks. Click on any task to be taken to the variants to review, or click on the radio button at the left of the task to mark the task as complete.
From within the Project: If a project has outstanding reviews to perform, an alert will be present at the top of all project pages. Click Review Task to be taken to the variants to review, or click the Mark as Completed button to mark it as complete.
When you open a review task, you are taken to the relevant variants in the Variants view, where the full annotation, external-resource, and conversation tools are available to support interpretation. Recording the team's assessment in a variant conversation keeps the reasoning attached to the variant for the future.
14.5. Completing tasks
As mentioned in Section 14.4, you can mark a task as complete from the Tasks page or by clicking Mark as Completed in the alert on the project page. Completed tasks are hidden by default on the Tasks page, and alerts will be removed from the project pages. You can find completed tasks on the Tasks page by setting the Status to Completed or removing the status filter completely.
14.6. Setting Up Reanalysis for Your Cases
ClinVar reanalysis is typically configured per group, usually at the collection level, in collaboration with the Frameshift team. To get the most from reanalysis:
- Choose which cases are included. Work with Frameshift to identify the projects or collections to enroll in reanalysis.
- Make sure phenotypes are recorded. Because the primary category depends on the proband's HPO terms, complete and accurate HPO terms directly affect how useful the notifications are.
- Set the notification recipients. Provide the email addresses that should receive update emails, and have the responsible team members subscribe for in-app tasks.
- Tune the criteria if needed. Adjust thresholds such as the allele-frequency cutoff to match the sensitivity your program wants.
Once configured, reanalysis runs automatically with each new ClinVar release, turning a previously manual, easily forgotten task into a continuous safety net for your undiagnosed cases.