3' Sliding Merge + Germline Event Clarification

[Satshil Rana]

Hello,

I wanted to reach out about a clarification for a 3' sliding event that happens alongside of a germline mutation. Image and description below:

There are 3 mutations in APC (NM_000038.5) which are in close vicinity, and would normally be merged into one variant. However, one of those is a germline variant which might disrupt the 3' Rule. Generally from what I've noticed about the 3' Rule, the ALT doesn't change if you apply the rule or you don't, which makes sense, that's the whole point of the rule. In the example below, a Germline mutation is making me pause and I'm unsure if the 3' rule should be applied or not.

The 3 mutations are:
5:112175766C>CCACAGAAA (Somatic)
5:112175770G>A (Germline)
5:112175775G>A (Somatic)

If we were to apply the 3' Rule, the ALT for all 3 merged together would be:
CCACCACAGAAAAGAAAA 

vs unmerged
CCACAGAAACACAGAAAA

Because of this, it doesn't make sense in my mind to apply the 3' rule.

I would love some clarification!

Thank you!

[Johan den Dunnen]

Dear Satshil,

to answer your question, some essential information is missing. I have to assume the reference sequence used is NC_000005.9 (hg19). I also assume that all variants are found on the same allele. When these assumptions are not correct, the descriptions I give may not be correct.

First, following HGVS nomenclature, a correct description of the first variant is NC_000005.9:g.112175769_112175770=/insAGAAACAC ("/insAG.AAACAC" for a somatic variant). 

When the allele has a G>A change at position g.112175770 the variant is described as NC_000005.9:g.112175770delinsAGAAACACA. In a combination of somatic/germline this is NC_000005.9:g.112175770G>A/delinsAGAAACACA.

Finally, in combination with the third variant NC_000005.9:g.[112175770G>A/delinsAGAAACACA;12175775=/G>A].

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op maandag 15 december 2025 om 15:38:02 UTC+1 schreef Satshil Rana: