ISO/TS 22693:2021

TECHNICAL ISO/TS
SPECIFICATION 22693
First edition
2021-06
Genomics informatics — Structured
clinical gene fusion report in
electronic health records
Informatique génomique — Rapport de fusion de gènes clinique
structuré pour les dossiers de santé électroniques
Reference number
©
ISO 2021
© ISO 2021
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ii © ISO 2021 – All rights reserved

Contents Page
Foreword .v
Introduction .vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 Abbreviated terms . 4
5 Gene fusion . 4
6 Composition of clinical gene fusion report . 5
6.1 General . 5
6.2 Summary section . 5
6.3 Detailed section . 5
7 Fields and their nomenclature of required data . 5
7.1 General . 5
7.2 Clinical sequencing order . 6
7.2.1 General. 6
7.2.2 Clinical sequencing order code . 7
7.2.3 Date and time . 7
7.3 Information on subject of care . 7
7.3.1 General. 7
7.3.2 Subject of care identifier . 8
7.3.3 Subject of care name . 8
7.3.4 Subject of care birth date . 8
7.3.5 Subject of care sex. 8
7.3.6 Subject of care ancestry . 8
7.3.7 Referring diagnosis . 8
7.4 Information on legally authorized person ordering clinical sequencing . 8
7.4.1 General. 8
7.5 Performing laboratory . 8
7.5.1 General. 8
7.5.2 Basic information on performing laboratory . 9
7.5.3 Information on report generator . 9
7.5.4 Information of legally confirmed person on sequencing report . 9
7.6 Biospecimen information . 9
7.6.1 General. 9
7.6.2 Type of specimen . 9
7.7 Fusion gene information. 9
7.7.1 General. 9
7.7.2 Gene and its partner gene information . 9
7.7.3 Chromosome information . 9
7.7.4 Breakpoints information. 9
7.8 Classification of variants . 9
7.9 Recommend treatment .10
7.9.1 General.10
7.9.2 Medication .10
7.9.3 Clinical trial information .10
7.9.4 Other recommendation .10
7.9.5 Supporting information .10
8 Fields and their nomenclature of optional data .11
8.1 General .11
8.2 Associated disease and phenotypes .11
8.3 Reference genome version .12
8.4 Genomic information related to race .12
8.5 Fusion gene information.12
8.5.1 Fusion gene ID .12
8.5.2 HGVS version .13
8.5.3 Fusion transcript image .13
8.5.4 Read counts for evidence reads (or supporting reads) .13
8.5.5 Count of total fusion events .14
8.5.6 Type of fusion .14
8.5.7 Validation using standard method (RT-PCR) .14
8.6 Detailed sequencing information .14
8.6.1 Clinical sequencing date .14
8.6.2 Quality control metrics .14
8.6.3 Sequencing platform information .14
8.6.4 Analysis platform information .15
8.7 References .15
Annex A (informative) Example structure of clinical sequencing report .16
Bibliography .21
iv © ISO 2021 – All rights reserved

Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
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electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/ directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
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World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see www .iso .org/
iso/ foreword .html.
This document was prepared by Technical Committee ISO/TC 215, Health informatics, Subcommittee
SC 1, Genomics informatics.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www .iso .org/ members .html.
Introduction
With the rapid advancement of next generation sequencing technologies, clinical sequencing has been
[1]
applied to realize precision medicine. ISO/TS 20428 aims at standardizing the clinical sequencing
reports in electronic health records but focuses on only DNA variations. However, the importance of
transcriptome information has been increased. The transcriptome is the complete set of all messenger
RNA molecules, which encode for the amino acid sequence of proteins. RNA sequencing gives us a large
amount of information on gene expression and RNA alterations in disease status. From a molecular
diagnostic standpoint, RNA-based measurements have the potential for broad application across
diverse areas of human health, including disease diagnosis, prognosis, and therapeutic selection.
A fusion gene is a hybrid gene made by the combination of two or more genes that had previously existed
independently. It is known to occur due to structural abnormalities of chromosomes such as insertion,
deletion, translocation, and inversion. Fluorescence in situ hybridization (FISH) has been used as
a gold standard as a method of detecting gene fusion in clinical practice but advances in technology
have enabled RNA-based detection of fusion genes that directly affect protein coding. One of the most
widely applied RNA-based technologies is qRT-PCR (Quantitative Reverse Transcription-Polymerase
Chain Reaction). The relatively inexpensive NGS (Next generation sequencing) method is actively used
in clinical practice as it detects many genes at once. There are DNA-based and RNA-based methods
for detecting fusion using NGS, but it is recognized that using RNA-based is more accurate in terms of
detection sensitivity.
Technological advancements have continually shaped the way that RNA-based (transcriptome)
measurements are used in the clinic. There are several commercially available RNA-based clinical tests.
[2]
In order to complement ISO/TS 20428, the RNA sequencing report is necessary. Among driver RNA
sequencing results, the most prevalent gene fusion was chosen as the first step. This document will aid
in developing other clinical RNA sequencing or whole transcriptome sequencing reports.
In this document, the data elements and their standardized metadata for gene fusion report using RNA
sequencing in electronic health records will be described. A structured clinical report for the fusion
gene will provide pertinent information on bioinformatics analysis to help clinical decisions.
vi © ISO 2021 – All rights reserved

TECHNICAL SPECIFICATION ISO/TS 22693:2021(E)
Genomics informatics — Structured clinical gene fusion
report in electronic health records
1 Scope
The document defines the data elements and their necessary metadata to implement a structured
clinical gene fusion report whose data are generated by next generation sequencing technologies.
This document
— describes the reporting guideline for RNA sequencing approaches focusing on detecting novel and
known fusion partners,
— defines the required data fields and their metadata for a structured clinical gene fusion report,
— defines the optional data fields and their metadata,
— covers the fusion gene from human specimen using whole transcriptome sequencing by next
generation sequencing technologies for clinical practice and translational research,
— does not cover the fusion gene detection using DNA sequencing methods,
— does not cover the basic research and other scientific areas,
— does not cover the other biological species,
— does not cover the Sanger sequencing methods, and
— does not cover the other structural variations.
This document only defines the data elements and their metadata for the structured clinical sequencing
report in electronic health records. Therefore, its layout can be designed based on the institutional
decision if all elements are included as in this document.
2 Normative references
The following documents are referred to in the text in such a way that some or all of their content
constitutes requirements of this document. For dated references, only the edition cited applies. For
undated references, the latest edition of the referenced document (including any amendments) applies.
ISO 8601 (all parts), Date and time — Representations for information interchange
ISO 20397-2:2021, Biotechnology — Massively parallel sequencing — Part 2: Quality evaluation of
sequencing data
ISO/TS 22220:2011, Health informatics — Identification of subjects of health care
ISO/TS 22692:2020, Genomics informatics— Quality control metrics for DNA sequencing
ISO/TS 27527:2010, Health informatics — Provider identification
HGNC: Bruford E.A., Braschi B., Denny P. et al. , Guidelines for human gene nomenclature. Nat Genet
52, 754–758 (2020). https:// doi .org/ 10 .1038/ s41588 -020 -0669 -3
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at http:// www .electropedia .org/
3.1
benign
alterations with very strong evidence against pathogenicity
[SOURCE: ISO/TS 20428:2017, 3.2]
3.2
biological specimen
biospecimen
specimen
sample of tissue, body fluid, food, or other substance that is collected or acquired to support the
assessment, diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical
state, or its symptoms
[SOURCE: ISO/TS 20428:2017, 3.34]
3.3
chromosome
structure that comprises discrete packages of DNA (3.5) and proteins that carries genetic information
which condense to form characteristically shaped bodies during nuclear division
[SOURCE: ISO 19238:2014, 2.7]
3.4
clinical sequencing
next generation sequencing or later sequencing technologies with human specimens (3.2) for clinical
practice and clinical trials
[SOURCE: ISO/TS 20428:2017, 3.5, modified — "samples" was changed to "specimens".]
3.5
deoxyribonucleic acid
DNA
molecule that encodes genetic information in the nucleus of cells
[SOURCE: ISO 25720:2009, 4.7]
3.6
fusion gene
gene (3.7) that is made by joining parts of two different genes that can occur naturally in the genome by
transferring DNA (3.5) between chromosomes (3.3)
3.7
gene
basic unit of hereditary material that encodes and controls the expression of a protein or protein
subunit
3.8
gene fusion
genetic recombination of the parts of two or more genes (3.7) resulting in a gene with different or
additional regulatory regions, or a new chimeric gene product
2 © ISO 2021 – All rights reserved

3.9
likely benign
alterations with strong evidence against pathogenicity
[SOURCE: ISO/TS 20428:2017, 3.22, modified — Note 1 to entry removed.]
3.10
likely pathogenic
alterations with strong evidence in favour of pathogenicity
[SOURCE: ISO/TS 20428:2017, 3.23]
3.11
pathogenic
characteristic that is objectively measured and evaluated as an indicator of normal biological processes,
pathogenic processes, or pharmacologic responses to a therapeutic intervention
[SOURCE: ISO/TS 20428:2017, 3.24]
3.12
read type
type of run in the sequencing instrument
Note 1 to entry: It can be either single-end or paired-end.
Note 2 to entry: Single-end: Single-end read runs the sequencing instrument reads from one end of a fragment to
the other end.
Note 3 to entry: Paired-end: Paired-end reads run from one end to the other end, and then start another round of
reading from the opposite end.
[SOURCE: ISO/TS 20428:2017, 3.27]
3.13
sequencing read
read
fragmented nucleotide sequences that are used to reconstruct the original sequence for next generation
sequencing technologies
[SOURCE: ISO/TS 20428:2017, 3.26]
3.14
reference sequence
nucleic acid sequence with biological relevance
Note 1 to entry: Each reference sequence is indexed by a one-dimensional integer coordinate system whereby
each integer within range identifies a single nucleotide. Coordinate values can only be equal to or larger than
zero. The coordinate system in the context of this document is zero-based (i.e., the first nucleotide has coordinate
0 and it is said to be at position 0) and linearly increasing within the string from left to right.
[SOURCE: ISO/IEC 23092-1:2020, 3.22]
3.15
ribonucleic acid
RNA
polymer of ribonucleotides occurring in a double-stranded or single-stranded form
[SOURCE: ISO 22174:2005, 3.1.3]
3.16
RNA sequencing
RNA-seq
technique that determines the complete or partial RNA (3.15) sequence of an organism's genome
3.17
subject of care
person who uses, or is a potential user of, a health care service
[SOURCE: ISO/TS 22220:2011, 3.2, modified — Admitted term and Note 1 to entry removed.]
3.18
target capture
method to capture genomic regions of interest from a DNA (3.5) specimen (3.2) prior to sequencing
[SOURCE: ISO/TS 20428:2017, 3.36, modified — "sample" was changed to "specimen."]
3.19
targeted RNA sequencing
technique that determines the RNA (3.15) sequence of interest in an organism's genome
3.20
variant of unknown significance
VUS
variation in a genetic sequence for which the association with disease risk is unclear
3.21
whole transcriptome sequencing
technique that determines the complete RNA (3.15) sequence of an organism's genome at a single time
4 Abbreviated terms
ACMG American College of Medical Genetics and Genomics
COSMIC Catalogue of Somatic Mutations in Cancer
EBI the European Bioinformatics Institute
FHIR Fast Healthcare Interoperability Resources
HGNC the HUGO Gene Nomenclature Committee
HGVS the Human Genome Variation Society
HUGO the Human Genome Organization
NCBI National Center for Biotechnology Information
NCCN National Comprehensive Cancer Network
NGS Next Generation Sequencing
SPREC Standard Preanalytical Code
WHO World Health Organization
5 Gene fusion
Gene fusion is a widespread phenomenon and “has been observed across all domains of life. Comparative
genomics studies reveal high and persistent incidence of gene fusions and identify lineage-specific
factors that promote or hinder the formation of chimeric genes. Studies of recent gene fusions expose
the mechanisms of their origin and the diversity of functional changes that accompany their formation.
Gene fusions prominently contribute to evolutionary change by providing a continuous source of new
genes. Gene duplications often precede gene fusions, permitting the evolution of chimeric genes, but at
the same time preserving the original functions. Despite the reputation of gene fusions as drivers of
4 © ISO 2021 – All rights reserved

adaptive evolution, gene fusions can have devastating consequences, often leading to genomic disorders
[8]
or cancer.”
[9]
The clinical use cases of gene fusion are well explained in NCCN guidelines. For example, Reference
[9] demonstrates how the identification of a fusion gene (ALK rearrangement) can guide therapeutic
decision. Several commercially RNA-based tests are available, but most of them use microarray or qRT-
PCR (Quantitative Reverse Transcription-Polymerase Chain Reaction). The first commercially available
RNA-based test using NGS technology was the gene fusion report.
6 Composition of clinical gene fusion report
6.1 General
The structured RNA fusion report may mainly consist of two parts, as in ISO/TS 20428: the summary
section and the detailed section. As defined in ISO/TS 20428, the summary section should include the
subset of required fields to help clinicians quickly overview the most significant findings. The detailed
section should contain all required fields (see Clause 7) and the selected optional fields (see Clause 8).
6.2 Summary section
The summary section should report the overall interpretation of a test based on clinical implication. It
should contain identified gene fusion information. The additional clinical significance with the relevant
therapies can be included. In addition, the summary section can include the subset of the detailed
section, as necessary.
6.3 Detailed section
The detailed section should contain all the required fields and the selected optional fields. The
required fields mainly focus on helping clinicians by providing the necessary gene fusion information,
interpretation results, and related treatments. They include all necessary fields for clinical practice.
The information that can be only described in the clinical sequencing report is included in the required
fields to minimize the length of clinical sequencing report. The optional fields provide more detailed
information to clinicians. They can also facilitate translational research with the necessary steps such
as de-identification or consent from the subject of care.
Annex A demonstrates the composition of the clinical gene fusion report by exemplifying the informative
values.
7 Fields and their nomenclature of required data
7.1 General
Data elements, their metadata, and cardinality are summarized in Table 1. The fields are chosen for
mainly clinical practice using gene fusion reports from RNA sequencing or whole transcriptome
sequencing. Cardinality represents that this data element shall appear once in the report (One) or
multiple times in the report (Many). Table A.1 demonstrates the example of required fields.
Table 1 — Data elements, their metadata, and cardinality for required fields
Data elements Metadata (Pri
...