Follow up regarding insertions that encode a translation stop codon

[David]

Dear HGVS team,

This question was originally posted as a reply to https://groups.google.com/g/hgvs-nomenclature/c/gxs9l_hDn98 , but I’m reposting it as a new topic to get more visibility.

I would like to follow up on the question I raised in May 2024 regarding the correct HGVS description of DNA insertions that encode a stop codon. At that time, you confirmed that such variants should be described as insertions, regardless of whether the inserted sequence length is a multiple of three.

However, this point remains a source of confusion within the community. Major tools such as Variant Validator, Mutalyzer, and VEP still appear to apply the "multiple of three" rule as the primary criterion for deciding between a frameshift and an insertion (or a delins), without considering whether the inserted sequence encodes a stop codon.

This suggests that the current HGVS guidelines are not sufficiently clear on this point. To help avoid inconsistent variant descriptions across tools, databases, and publications, I would like to kindly reiterate my request for clarifying the guidelines.

Kind Regards,
David Hernandez

Sophia Genetics SA

https://www.sophiagenetics.com/

[Fokkema, I.F.A.C. (HG)]

Dear David,

I had added your concern to today's HVNC meeting's agenda, but we ran out of time before we got to discussing your email. Would you be willing to start a discussion on our GitHub page on this subject?

https://github.com/HGVSnomenclature/hgvs-nomenclature/discussions/new?category=hgvs-nomenclature-proposals

I believe this is an important subject, and starting a discussion on GitHub is the first step towards a possible update of the HGVS Nomenclature.

Thank you,

Ivo Fokkema

HGVS Variant Nomenclature Committee

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From: hgvs-nom...@googlegroups.com <hgvs-nom...@googlegroups.com> on behalf of David <david.g.h...@gmail.com>
Sent: Tuesday, September 23, 2025 17:10
To: HGVS Nomenclature <hgvs-nom...@googlegroups.com>
Subject: [hgvs-nomenclature] Follow up regarding insertions that encode a translation stop codon

 

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