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.

Pathogenic

In order for a variant to be classified as pathogenic, the following criteria have to be fulfilled.

1. There is strong evidence for the PVS1 null variant criterion being fulfilled in conjunction with:
   1. 1 strong PS1-4 criterion or
   1. 2 moderate PM1-PM6 criterion being true or
   1. 1 moderate PM1-PM6 criterion is true and 1 supporting PP1-PP5 criterion or
   1. 2 or more supporting criteria PP1 – PP5 are true
2. 2 or more strong PS1-PS4 criteria are true
3. 1 strong PS1-PS4 criterion and:
   1. 3 or more  moderate PM1-PM6 criteria are true or
   1. 2 moderate PM1-PM6 and two or more supporting criteria PP1-PP5 or
   1. 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.

Likely Pathogenic

The likely pathogenic classification has high clinical relevance. It makes stronger use of supporting criteria. A variant is likely pathogenic given the following:

1. There is strong evidence for a PVS1 null variant and  1 moderate PM1 – PM6 criterion or
2. 1 strong PS1-PS4 and 1-2 moderate PM1-PM6 criteria or
3. 1 strong PS1-PS4 and 2 or more supporting criteria PP1-PP5 or
4. 3 or more moderate criteria PM1-PM6 or
5. 2 moderate PM1-PM6 and 2 or more supporting criteria PP1-PP5 or
6. 1 moderate criterion PM1-PM6 and 4 or more supporting criteria PP1-PP5

Benign

The criteria for a benign classification are essentially very straightforward:

1. 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.
2. There are 2 or more strong criteria BS1-BS4 fulfilled.

Likely Benign

The likely benign category makes use of supporting evidence. A variant is categorized as likely benign if the following is given:

1. 1 strong criterion BS1-BS4 is true and 1 supporting evidence can be found BP1-BP7 or
2. 2 or more supporting criteria BP1-BP7 are evident

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