Rules for Combining Various Classification Criteria
Now that we have a solid understanding of how the various criteria are meant to be applied, it’s time to look at how the evidence collectively leads to the clinical categorization of a variant. Let’s go through the rule framework for combining the various criteria.
In order for a variant to be classified as pathogenic, the following criteria have to be fulfilled.
is strong evidence for the PVS1 null variant criterion being fulfilled in conjunction with:
- 1 strong PS1-4 criterion or
- 2 moderate PM1-PM6 criterion being true or
- 1 moderate PM1-PM6 criterion is true and 1 supporting PP1-PP5 criterion or
- 2 or more supporting criteria PP1 – PP5 are true
- 2 or more strong PS1-PS4 criteria are true
- 1 strong PS1-PS4 criterion
- 3 or more moderate PM1-PM6 criteria are true or
- 2 moderate PM1-PM6 and two or more supporting criteria PP1-PP5 or
- 1 moderate PM1-PM6 and four or more supporting criteria PP1-PP5
In all of this, it should be explicitly stated that without clear literature evidence, a variant should never be classified as pathogenic.
The likely pathogenic classification has high clinical relevance. It makes stronger use of supporting criteria. A variant is likely pathogenic given the following:
- There is strong evidence for a PVS1 null variant and 1 moderate PM1 – PM6 criterion or
- 1 strong PS1-PS4 and 1-2 moderate PM1-PM6 criteria or
- 1 strong PS1-PS4 and 2 or more supporting criteria PP1-PP5 or
- 3 or more moderate criteria PM1-PM6 or
- 2 moderate PM1-PM6 and 2 or more supporting criteria PP1-PP5 or
- 1 moderate criterion PM1-PM6 and 4 or more supporting criteria PP1-PP5
The criteria for a benign classification are essentially very straightforward:
- 1 stand-alone BA1 criterion is fulfilled, which means the variant can be found in the standard population level catalogs at a frequency that rules out pathogenicity.
- There are 2 or more strong criteria BS1-BS4 fulfilled.
The likely benign category makes use of supporting evidence. A variant is categorized as likely benign if the following is given:
- 1 strong criterion BS1-BS4 is true and 1 supporting evidence can be found BP1-BP7 or
- 2 or more supporting criteria BP1-BP7 are evident
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