IMPORTANT - KMT2A Partial Tandem Duplication (PTD) HGVS nomenclature guidance request from an EQA/PT service provider
Debbie Travis
Re: IMPORTANT – KMT2A Partial Tandem Duplication (PTD) HGVS nomenclature guidance request from an EQA/PT service provider
Dear HGVS Team/Community,
I am hoping you will be able to advise regarding the suitability and possible application of HGVS based nomenclature in the context of KMT2A (MLL) Partial Tandem Duplication (PTD).
I am contacting you as a Clinical Scientist working for UK NEQAS, a not-for-profit organisation providing External Quality Assessment (EQA)/Proficiency Testing (PT) services. Please refer to the UK NEQAS website for additional information about who we are and what we do:
I am involved with delivering the UK NEQAS LI Myeloid Gene Panels EQA/PT programme, which is undertaken by UK laboratories and international participants. Further information about the UK NEQAS LI centre and the Myeloid Gene Panels programme can be found on our website:
- https://www.ukneqasli.co.uk/about-us/
- https://www.ukneqasli.co.uk/eqa-pt-programmes/molecular-haemato-oncology-programmes/myeloid-gene-panels-pilot-not-accredited/
As part of an educational EQA/PT trial we recently distributed material from an Acute Myeloid Leukaemia (AML) case found to harbour a KMT2A PTD. I am seeking your recommendations regarding the best practice application of HGVS nomenclature in this scenario; our participants have specifically requested guidance with this aspect of reporting.
There is some discussion in the literature regarding KMT2A (MLL) gene structure: https://www.nature.com/articles/s41375-024-02261-3
Nevertheless, for our EQA/PT programme we are currently working to GRCh38 and the MANE Select transcript (NM_001197104.2)
For general information about the detection of KMT2A PTD via targeted Next Generation Sequencing (NGS) panels (amongst other techniques), the following publication may be of interest: https://pubmed.ncbi.nlm.nih.gov/38730645/
KMT2A PTD breakpoints typically occur within the intronic sequence. Frequently the targeted gene panel NGS results obtained by laboratories can indicate a duplication event (via coverage comparison) involving a given number of KMT2A exons but will not fully characterise the breakpoints in detail (introns are often not fully encompassed by the sequencing assay design and/or short reads can be restricting).
For patient clinical reports, the description of variants (single nucleotide variants, small ins/dup/del events) detected by tumour focused NGS (performed on genomic DNA) are typically provided at the cDNA level. If appropriate, an accompanying protein prediction is also included. If laboratories are wishing to maintain consistency and describe a KMT2A PTD at the cDNA level (we acknowledge there are some flaws to this approach) please could you provide guidance on the best approach?
I note your general advice regarding a duplication for which the breakpoint has not been fully elucidated: https://hgvs-nomenclature.org/stable/recommendations/uncertain/
(A_B)_(C_D)dup
B, C = minimal extent of the duplication
A, D = maximal extent of the duplication
g.(last-normal_first-duplicated)_(last-duplicated_first-normal)dup
And also, the use of ? (question mark) to indicate unknown positions (nucleotide or amino acid).
Therefore, would it be acceptable at the cDNA level to describe a KMT2A PTD known to involve at least the whole exons 2-10 (NM_001197104.2) using the following approach:
c.(?_5’ [first] nucleotide exon 2)_( 3’ [last] nucleotide exon 10_?)dup
NM_001197104.2:c.(?_433)_( 3’ 4332_?)dup
In the example above we have assumed evidence is sufficient to indicate a duplication event in tandem (not an insertion).
Should we be encouraging participants to also describe KMT2A PTDs using HGVS at the genomic level?
Alternatively, should ISCN (chromosome structure) be preferentially utilised to describe a KMT2A PTD (typically approx. 40 kb -50 kb duplicated gene segment) rather than HGVS nomenclature?
Nomenclature for KMT2A PTDs is an area in need of a unified standardised approach to ensure the effective communication of clinically actionable results both to the medical teams caring for patients and between laboratories providing testing. Your support and guidance would be hugely appreciated by our participating laboratories.
With many thanks and very best wishes
Debs
Dr Debbie Travis
Clinical Scientist, UK NEQAS for Leucocyte Immunophenotyping
South Yorkshire & Bassetlaw Pathology Service
Tel: +44 (0) 114 2673600
Contact: debbie...@ukneqasli.co.uk | ad...@ukneqasli.co.uk | MS Teams
Address: UK NEQAS for Leucocyte Immunophenotyping, 4th Floor, Pegasus House,
463a Glossop Road, Sheffield, S10 2QD, United, Kingdom
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You can also contact me via: debbie...@nhs.net but please note that this inbox is not so frequently monitored
Ros Hastings
9.4.2.3 Duplication examples vi and vii:
ogm[GRCh38] 11q23.3(118,341,120_118,349,783)×3[0.6]
or
ogm[GRCh38] dup(11)(q23.3q23.3)(118,341,120_118,349,783)[0.6]
Genome mapping shows intragenic duplication of part of KMT2A within 11q23.3 in 60% of a neoplastic sample. This represents a simple canonical KMT2A partial tandem duplication. KMT2A is not listed in the ISCN description because only part of the gene is duplicated (see Section 9.3).
ogm[GRCh38] 11q23.3(118,341,120_118,526,842)(KMT2A)×3[0.6]
or
ogm[GRCh38] dup(11)(q23.3q23.3)(118,341,120_118,526,842)(KMT2A++)[0.6]
Genome mapping shows duplication of the KMT2A gene within 11q23.3 in 60% of a neoplastic sample. Note: the first option uses the short system (microarray format) and does not provide structural information. It shows that there are three copies of KMT2A in 60% of the sample. The second option uses the short system (karyotype format) and shows that there are two copies of KMT2A on one of the chromosome 11 homologues.
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debbie...@ukneqasli.co.uk
Dear Ros
Thanks ever so much for your email, really appreciate it.
Unfortunately, I don’t have access to the full ISCN 2024 currently. It’s not a system I’ve a huge amount of direct experience using; especially the 2024 revision. I’ve spotted Moore et al. (2024) regarding genome mapping ISCN nomenclature. I will also feedback your guidance in the trial report.
Yes please, to some assistance in writing the ISCN nomenclature for sequencing, thank you (very happy to acknowledge your advice in the trial report). Are you able to share ISCN (2024) Chapter 11 with me at all? I’d like to do some homework first; based on Chia et al. (2025) it looks like this chapter would be very helpful.
If your HGVS colleagues could also comment on the c. format approach (requested by participants) that would be really helpful too. I’ve searched for a KMT2A PTD or similar example (breakpoints not fully characterised) on the HGVS website but have not spotted anything specific (v21.1.3).
Initial suggestion KMT2A PTD (exon 2-10):
c.(?_5’ [first] nucleotide exon 2)_( 3’ [last] nucleotide exon 10_?)dup
NM_001197104.2:c.(?_433)_(4332_?)dup
Sorry, there was a copy typo in my first mail, ‘3’’ should have been removed in the final example, now corrected here (and in the string below).
Further suggestion KMT2A PTD (exon 2-10):
Searching on the HGVS website further, considering the approach described for multiplex PCR based techniques (breakpoints not characterised), the KMT2A PTD (exon 2-10) perhaps could be described as below. It communicates a bit more information as to the known maximum limit of the segment involved in the tandem duplication.
The variant is described based on the last sequenced coding nucleotide of exon 1 (c.432), the first duplicate sequenced coding nucleotide of exon 2 (c.433), the last duplicate sequenced coding nucleotide of exon 10 (c.4332), and the first sequenced coding nucleotide of exon 11 (c.4333).
NM_001197104.2:c.(432_433)_(4332_4333)dup
This would be GRCh38 (Chr 11) g.(118436944_ 118468775)_(118484975_118488614)
In this example we have (1) assumed evidence is sufficient to indicate a duplication event in tandem (not an insertion) and (2) the NGS results indicated no copy number gain for the coding regions of exon 1 and exon 11.
Participants will be running various NGS panel designs (encompassing the KMT2A intronic regions to a varying degree, different read lengths and assembly tools). Myeloid Gene Panels is a pilot programme (benchmarking by consensus), only a couple of participants attempted a HGVS description for the KMT2A PTD (all different). We won’t be able to offer definitive c./g. nomenclature (breakpoints defined) for this EQA case, but I know some support and general pointers would be really welcomed in the trial report.
I am a big advocate for standardised nomenclature systems (we have done a lot of educational work on this for SNVs and small del/dup/ins). However, in instances like this, I understand that also including a basic description of the event such as ‘KMT2A PTD (exon 2-10)’ is useful to the haematologist/clinical team.
With thanks and very best wishes
NM_001197104.2:c.(?_433)_(4332_?)dup
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Johan den Dunnen
> KMT2A PTD (exon 2-10)
> c.(?_5’ [first] nucleotide exon 2)_( 3’ [last] nucleotide exon 10_?)dup
> NM_001197104.2:c.(?_433)_(4332_?)dup
Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)