The PP5 and BP6 were suggested by the original 2015 guidelines to be applied in the case that “a variant was reported pathogenic (PP5) or benign (BP6) variant and evidence is not available”.

It was later in 2018 it was suggested to remove these rules, due to the possibility of double counting. Meaning that the reported classification for pathogenic or benign, is based on the same current evidence, and therefore it should not be used as additional evidence.

To align with these updated recommendations, Franklin extracts evidence of pathogenicity from submitters in ClinVar. This may be based on their supporting text or evidence shared about their patients.

The evidence includes de-novo occurrences (PS2 rule), presence in affected individuals with the variant in a homozygous state, compound heterozygosity, or in trans with another pathogenic variant in recessive conditions (PM3 rule), functional studies supporting the pathogenicity of the variant (PS3 rule), segregation evidence (PP4 rule), and observations of the variant in affected individuals in dominant conditions (PS4 rule).

In these cases, Franklin will give details of why it applied these rules under the rules' details.

In the case that this information is supplied and we apply this evidence, we will apply PP5 without giving it strength in order to avoid double counting the evidence. Yet we will highlight that there is evidence coming from ClinVar.

When such evidence is provided, we apply the PP5 rule without assigning additional strength to it, to avoid double counting. However, we do highlight that this evidence is sourced from ClinVar.

This will presented as “No influence” strength.

In cases where Franklin does not specifically extract the evidence, or when additional evidence is not attached, external classified variant databases like ClinVar are still heavily relied upon in clinical practice and are considered robust evidence for variant classification. This holds true even when no evidence is provided by the submitter.

Having said that, it is important to note that not all submissions should be treated the same. Some sources and submitters are more reliable than others, older submissions should be treated more cautiously than newer submissions, as well as other features including the number of supporting submissions and conflicts that can also be used for reliability.

In order not to miss this important evidence, Franklin applies the PP5/BP6 rules while the strength of the rules is determined based on the level of evidence. For example, an old submission (before 2015) reported as LP will be given a supporting evidence weight, while variants with multiple newer submissions will be given strong evidence.

PS1 and PM5

The PS1 and PM5 rules should be applied in the case of a missense variant, where its amino change affects the same amino acid change as a known pathogenic variant (but not the same variant).

The difference between the two rules is that PS1 requires that the variant would result in the exact same amino acid as the known pathogenic variant causes, while PM5 meant it results in a different amino acid change than the known pathogenic variant.

Franklin considered “known pathogenic” variants for which the rules will be applied to, previously reported pathogenic variants in databases similarly as in the PP5/BP5 rules such as ClinVar, UniProt, Genoox, etc.

Also in a similar way to the PP5/BP6 rules, different weights will be assigned to the PS1/PM5 rules based on the level of pathogenicity of the reported “known” variant. So PS1 can be given an evidence weight ranging from Supporting to Strong, while PM5 evidence weight can range between Supporting to Moderate.