Germline variant - should it be seen in the somatic vcf?

Question

[amy__]

Hello,

Sorry if this is a basic question. I have a germline variant, when looking at the somatic vcf - would I expect to see that variant also present? For example in the context of a two-hit, would that first germline variant be present in the somatic vcf?

Thanks! Amy

[Ram]

What's a two hit?

By definition, a somatic variant cannot be a germline variant. You can include both in your variants of interest, but somatic variants are those present in tumor cells that are not present in germline cells. According to https://gatk.broadinstitute.org/hc/en-us/articles/360035890491-Somatic-calling-is-NOT-simply-a-difference-between-two-callsets,

Technically speaking, somatic variants are both (i) different from the control sample and (ii) different from the reference. What this means is that if a site is variant in the control but in the somatic sample reverts to the reference allele, then it is not a somatic variant.

EDIT: I don't know what the two-hit hypothesis has to do with this. It means both alleles of tumor suppressor genes need to be mutated. I'm not sure if one of them can be germline (technically it could be).

[amy__]

Hi, sorry I am looking at tumour suppressor genes. I have identified a germline loss-of-function variant and have somatic sequencing of the tumours also - I was wondering if in the somatic, I should also see the variant found in the germline sequence. In some AD tumour syndromes the initial hit is in the germline, for example with APC related polyposis (Familial adenomatous polyposis). Thanks!

[Ram]

Biological questions are beyond my expertise - I deal largely with CS related stuff. As far as I can think about this, if you see a germline variant in a cancer cell, it does not qualify as a somatic variant. Again, this is a technical term. You can look at a set of variants of interest that allows for germline variants that you think are relevant as long as you qualify them as germline (the only purpose that serves is that it logs information that it is not somatic but you included it anyway). You could also add an INFO/comments field that logs why you chose to add that variant. The advantage of using such a field it that you have a log within the VCF. On the other hand, if you're working with an MAF file, you should also be able to add a column that holds comments.

Ultimately, it comes down to your biological question. All these labels are helpful in addressing that question. Use them wisely but don't let them limit you.