Additional changes to Draft 1 - Paolo Campregher Feedback

[ahwagner]

Please use this form to provide feedback for the cross-consortium Gene Fusion guidelines at fusions.cancervariants.org.

Name Paolo Campregher

What draft version are you leaving feedback on? draft-1

Please provide any comments you have on the guidelines

Terminology

1. I consider the following sentence problematic: “Gene products that are considered loss-of-function or are not expressed should not be described as gene fusions, even when they result from a genomic rearrangement.” The function of the fusion (gain or loss of function) was not addressed in the definition previously given (the interaction of two or more genes to drive aberrant activity of a gene product, through formation of a chimeric transcript or interaction of rearranged gene regulatory elements.), therefore, it is problematic to include gain or loss of function here to classify an event as a fusion. In many cases we do not know the function of the identified event. I am going to give a practical example. We have identified in a cancer patient through targeted RNA sequencing the chimeric transcript STAT5B-BRCA1. This transcript is the result of a fusion between a portion of 5’ UTR of STAT5B with BRCA1 exon 20. We considered it to be a VUS, but a fusion event nevertheless. If this is not considered a fusion, what should we call it? Also, if we look in the literature, the thousands of chimeric events identified through RNASEQ in several tumor types are considered fusions independent of its function. In my opinion, we should either remove this sentence to keep the definition broad, or we could modify the sentence as following: ”Gene products that are considered loss-of-function or are not expressed should not be described as gene fusions, even when they result from a genomic rearrangement.”
2. I would rephrase “Gene fusions are closely related to, but distinct from many related types of variation”, to “Gene fusions are closely related to, but distinct from other types of variation”

Minimum Information Model

Assay

1. Regarding fusion detection methods, is think there is not a direct method for detecting regulatory fusions, correct? Maybe this should be stated in the box.

[ahwagner]

Broad consensus that gain/loss of function is not relevant criteria for considering a variation a gene fusion.

[ahwagner]

Consensus from 6/22 call: our guidelines should reflect our consensus that we consider today's assays to primarily detect regulatory fusions by inference.