Data Element
Variant Clinical Significance
Description

Clinical significance is an assessment of the magnitude of a genetic variant's clinical effects as per estimates supplied by researchers and/or guidelines (source: HL7 Clinical Genomics Working Group).
Submitted By: May Terry / MITRE Corporation
Data Element Information
Rationale for Separate Consideration The USCDIv4 Laboratory class lists a result interpretation element which might be considered. However, clinical significance is different from a simple interpretation of other types of lab results that are chemistry or hematological. The clinical significance categories are unique for the identified variant and may change over time as genomic knowledgebases are updated with new genotype-to-phenotype discoveries.
Use Case Description(s)
Use Case Description The CodeX GenomeX domain data exchange and operations use cases aim to build standardized and scalable FHIR® Genomics interfaces, therefore enabling appropriate data to be sent to EHRs or genomics repositories. The GenomeX members include representatives from government, life sciences, industry, and health care provider organizations.

The specific use case involves a genomics reference lab sending report results which include molecular variants and a clinical significance that identifies whether the variant is pathogenic, benign, or of unknown significance. This is different from a simple interpretation of other types of lab results that are chemistry or hematological because it these clinical significance categories for the identified variant may change over time as genomic knowledge-bases are updated with new genotype-to-phenotype discoveries.
Estimate the breadth of applicability of the use case(s) for this data element The submission is Level 1 since it is used in several clinical domains including oncology, neurology, and cardiology.
ONC Priority
  • Address public health interoperability needs of reporting, investigation, and emergency response
Maturity of Use and Technical Specifications for Data Element
Applicable Standard(s) LOINC is the reference terminology proposed by the HL7 Genomics Reporting FHIR IG (http://hl7.org/fhir/uv/genomics-reporting/index.html) for codifying the ACMG clinical significance categories (https://loinc.org/LL4034-6/)
https://loinc.org/LL4034-6
Additional Specifications • The HL7 Genomic Reporting FHIR® IG Diagnostic Implication profile specifies a data element for clinical significance with a LOINC value set which includes AMP/ACMG categories for clinical significance.

• HL7 Version 2.5.1 Implementation Guide: Laboratory Results Interface Release 1, STU Release 4 – US Realm, Chapter 6, specify clinical genomics results reporting elements which includes the clinical significance data element.

• The American Molecular Pathology (AMP) and American College of Medical Genetics and Genomics (ACMG) released a joint consensus recommendation on the interpretation of sequence variants which includes the categories for clinical significance.
Current Use (Level 0) Captured, stored, or accessed in limited settings such as a pilot or proof of concept demonstration
Extent of exchange (Level 1) Between two production EHRs or other HIT modules using available interoperability standards
Supporting Artifacts HL7v2-based data exchange of genetic results from a genomics reference lab to an EHR are currently supported in production environments, most recently in genomics data exchange between the Tempus genomics reference lab and Vanderbilt University Medical Center Epic EHR (https://www.tempus.com/news/pr/tempus-and-vanderbilt-ingram-cancer-center-announce-data-initiative-to-improve-outcomes-for-cancer-patients/).

Additionally, this exchange was demonstrated as a proof of concept in the HL7 May 2023 FHIR Connectathon (https://confluence.hl7.org/display/FHIR/2023+-+05+Clinical+Genomics) where FHIR resources created by at least one genomic reference lab was sent to the Epic EHR.
https://www.tempus.com/news/pr/tempus-and-vanderbilt-ingram-cancer-center-announce-data-initiative-to-improve-outcomes-for-cancer-patients/
Potential Challenges
Restrictions on Standardization (e.g. proprietary code) There are no restrictions on the standardization of this data element. All models and codes are available for public use.
Restrictions on Use (e.g. licensing, user fees) There are no restrictions on the use of this data element.
Privacy and Security Concerns There are no privacy and/or security concerns on the exchange of this element.
Estimate of Overall Burden There is minimal burden to exchange a variant clinical significance because this element is found in many genomic somatic reports, especially in oncology where oncologists need to know whether a variant is benign or pathogenic.
ONC Evaluation Details
Each submitted Data Element has been evaluated based on the following criteria. The overall Level classification is a composite of the maturity based on these individual criteria. This information can be used to identify areas that require additional work to raise the overall classification level and consideration for inclusion in future versions of USCDI
Criterion #1
Maturity - Current Standards		 Level 2 - Data element is represented by a terminology standard or SDO-balloted technical specification or implementation guide.
Criterion #2
Maturity - Current Use 		Level 0 - Data element is captured, stored, or accessed in limited settings such as a pilot or proof of concept demonstration.
Criterion #3
Maturity - Current Exchange		 Level 1 - Data element is electronically exchanged between two production EHRs or other HIT modules using available interoperability standards.
Criterion #4
Use Case(s) - Breadth of Applicability		 Level 0 - Use cases apply to a limited number of care settings or specialties, or data element represents a specialization of other, more general data elements.
Evaluation Comment This data element is a specialized use of an existing USCDI v4 data element Values/Results in the Laboratory data class.

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