Question about HGVS nomenclature

[CABEZON MARCO, MARTA]

Dear Sirs and Madams,

We found by NGS 3 variants in cis in the gene BCOR (NM_001123385.1), one deletion (likely pathogenic, LP) and 2 SNV (likely benign, LB), where the deletion are together and there is a separation by one nucleotide with one of the SNV (see image attached):

1. X:39922008 G C BCOR(NM_001123385.2):c.4164C>G; p.(Ala1388=)
2. X: 39922012; BCOR; c.4158_4159del; p.Asn1387CysfsTer21
3. X: 39922016; BCOR; c.4156G>A; p.Glu1386Lys

 

 

My questions is: according to HGVS, where substitutions involving two or more consecutive nucleotides are described as deletion/insertion (delins) variants, but  two variants separated by one or more nucleotides should be described individually and not as a "delins" of the sequence affected. (Exception: two variants separated by one nucleotide, together affecting one amino acid, should be described as a "delins") variants 2 and 3 should be described separately or together as a delins?

If they are described as a unique delins, it stays (LP):

• X:39922014_39922016delinsT; c.4156_4158delinsA; p.(Glu1386LysfsTer22)

Which one do you think is more correct with the actual HGVS nomenclature?

Thank you very much in advance for your help.

Best regards,

Marta Cabezón Marco

Unitat Biologia Molecular - Laboratori d'Hematologia

Institut Català d'Oncologia - Hospital Germans Trias i Pujol

Telf: 93.497.88.68 (ext.3697)

[Johan den Dunnen]

Dear Marta,

the predicted consequences on protein level of NM_001123385.2:c.4156G>A are affected by variant c.4158_4159del (deleting the last nucleotide of the codon). Similarly, due to the upstream frame shift, the predicted consequence of c.4164C>G is not p.(Ala1388=). Therefore, it seems best to describe the variant as NC_000023.11:g.40062755_40062763delinsCGCATTT NM_001123385.1:c.4156_4164delinsAAATGCG p.(Glu1386LysfsTer22). 

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op donderdag 26 februari 2026 om 09:40:00 UTC+1 schreef CABEZON MARCO, MARTA:

[CABEZON MARCO, MARTA]

Thank you very much for your response, Dr. Johan den Dunnen.

This nomenclature was also our first choice; however, last month we participated in the European Quality Control UK NEQAS (Myeloproliferative Neoplasm Diagnostic Testing Programme), where a similar alteration in JAK2 was included (see attached image).

 

The trial comments that Sample MPN DT 125 comprised genomic DNA extracted from an MPN patient known to harbour the NM_004972.4:c.1624_1629del p.(Asn542_Glu543del) JAK2 exon 12 somatic variant. This 6 bp in-frame deletion has previously been described in the literature. The single base substitution c.1632T>C p.(Asp544=) was also present in cis in this sample. According to HGVS nomenclature guidelines, two variants separated by one or more nucleotides should be described individually and not as a “delins”. JAK2 c.1632T>C p.(Asp544=) represents a silent synonymous change and, when considered together with the c.1624_1629del variant, does not affect the protein description. The c.1632T>C p.(Asp544=) variant is therefore not regarded as clinically significant nor relevant for submission in this trial.

For this reason, we had doubts about how to name the BCOR variant we previously asked you about.

With all this in mind, what do you think would be the correct nomenclature, according to the updated HGVS guidelines, for the JAK2 variant we are presenting?

• c.1624_1629del + c.1632T>C (synonymous change that should not be reported)
• c.1624_1632delinsGAC

 

Thank you in advance for your time and consideration.

Marta Cabezón Marco

Unitat Biologia Molecular - Laboratori d'Hematologia

Institut Català d'Oncologia - Hospital Germans Trias i Pujol

Telf: 93.497.88.68 (ext.3697)

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De: CABEZON MARCO, MARTA
Enviat el: dijous, 26 de febrer de 2026 9:39
Per a: hgvs-nom...@googlegroups.com <hgvs-nom...@googlegroups.com>
A/c: DE AGUIRRE EGAÑA, ITZIAR <iagu...@iconcologia.net>; MARCE TORRA, SILVIA <sma...@iconcologia.net>; PALOMO SANCHIS, LAURA <lpa...@iconcologia.net>; RAMIREZ SERRANO, JOSE LUIS <jram...@iconcologia.net>; ZAMORA PLANA, LURDES <lza...@iconcologia.net>
Tema: Question about HGVS nomenclature

 

[Santcroos, M.A. (HG)]

Dear Marta, Johan, all,

The HGVS recommendation about allele descriptions are ambiguous at best. 

In recent work we came up with a deterministic method for variant extraction and description based on the actual alignments: https://academic.oup.com/nargab/article/7/4/lqaf173/8373945

For the BCOR example with input NM_001123385.2:c.[4156G>A;4158del;4164C>G] the result of our method is NM_001123385.2:c.[4156_4158delinsA[2];4164C>G].

Below are the sequence visualization and the alignment graph of all the minimal alignments. Here we can see that 4156G>A + 4158del have interfering alignments and should not be reported individually.

The third variant 4164C>G remains isolated though.

More information about this variant: https://test.mutalyzer.nl/normalizer/NM_001123385.2:c.%5B4156G%3EA;4158del;4164C%3EG%5D

For the JAK2 example NM_004972.4:c.[1624_1629del;1632T>C] the output of out method is NM_004972.4:c.1624_1632delinsGAC.

Below the sequence visualization and the alignment graph. Here we can see that the variants can not be seen in isolation and should be reported as one.

More information for this variant: https://test.mutalyzer.nl/normalizer/NM_004972.4:c.%5B1624_1629del;1632T%3EC%5D

I see questions like yours come up more regularly on this mailing list, and we hope to be able to provide a more deterministic approach to answering the question of how multiple variants in cis should be reported.

Please let me know if you have more questions on this or would like more background.

Regards,

Mark

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From: 'CABEZON MARCO, MARTA' via HGVS Nomenclature <hgvs-nom...@googlegroups.com>
Sent: Friday, February 27, 2026 4:02 PM
To: hgvs-nom...@googlegroups.com <hgvs-nom...@googlegroups.com>
Cc: DE AGUIRRE EGAÑA, ITZIAR <iagu...@iconcologia.net>; MARCE TORRA, SILVIA <sma...@iconcologia.net>; PALOMO SANCHIS, LAURA <lpa...@iconcologia.net>; RAMIREZ SERRANO, JOSE LUIS <jram...@iconcologia.net>; ZAMORA PLANA, LURDES <lza...@iconcologia.net>
Subject: [hgvs-nomenclature] Re: Question about HGVS nomenclature

 

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[Johan den Dunnen]

Dear Mart,

following HGVS nomenclature, the JAK2 case can be best described as NC_000009.12:g.[5070035_5070040del;5070043T>C] NM_004972.4:c.[1624_1629del;1632T>C]. The main difference with the BCOR case is that the deletion does not alter the reading frame so does not affect the predicted consequences of variant c.1632T>C. Therefore, the recommendation "two variants separated by one or more nucleotides should be described individually" can be followed.

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op zaterdag 28 februari 2026 om 10:10:43 UTC+1 schreef m.a.sa...@lumc.nl: