add discussion of differences in somatic and germline interpretation

[ahwagner]

It is also important, in the introduction, and indeed for the presentation of information in the collated database, for the authors to be clear that the variant interpretation processes for germline and somatic are quite different, and what it means in terms of determining if a specific variant versus a specific variant type is indicated for a drug treatment. The AMP/ASCO/CAP evidence guidelines do not address the relevance of variant effect in the interpretation of therapeutic. This is a critical difference to eg the ACMG guidelines set up for interpretation of germline variants, and, in the opinion of this reviewer, a critical gap in the presentation and application of the AMP/ASCO/CAP guidelines. If for example Olaparib is indicated for treatment of breast or ovarian cancer patients who carry loss-of-function BRCA1 or BRCA2 variants, then there is no great value in knowing exactly which variants were carried by patients in the original trials, or listing in a database the 1000’s of loss of function BRCA1/2 variants seen in clinical practice for diagnosis/presymptomatic management.

[ahwagner]

Initial comments: Adam Margolin:

I think the reviewer is making 2 different points here, so breaking this comment in 2. For this one, we should just do what he asks and add a few sentences to the introduction talking about the differences between germline and somatic variants and which databases contain what and how this information is used differently. We can add this to the text we will write for the point above. And in the introduction where we talk about differences between prognostic, diagnostic, predictive, etc. we can also write a little about differences in different types of variants, including germline and somatic.

Anonymous:

Making our focus on somatic is something we discussed a lot when bringing the paper together so agree with this approach

[ahwagner]

Dmitriy Sonkin:

AMP/ASCO/CAP guidelines paper touches on relevance of variant effect in the interpretation of therapeutic relevance, however it does not provide structured guidelines for assessment of variant pathogenicity. In response we can say that AMP is aware of feedback from community and it's working with ACMG, ClinGen, VICC on developing guidelines for interpretation of pathogenicity/oncogenicity of somatic variants and incorporating such guidelines in updated version of AMP/ASCO/CAP guidelines.

Jacqui Beckmann:

While I agree that it will improve the ms to discuss the differences between these two types of variants (yes we should definitely do it) I feel that it is way too premature to come out with strong recommendations as the ACMG has done. It has taken them a while to gather solid evidence to make such recommendations. This will happen for somatic variants too, but we have to be patient and avoid the risk of possibly misleading interpretations.