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Representation of classifications in ClinVar

Types of classifications

ClinVar represents three types of variant classifications:

  • Classification of germline variants for Mendelian diseases and drug responses
  • Classification of somatic variants for clinical impact
  • Classification of somatic variants for oncogenicity

A submitted record (SCV) represents a single type of classification. A submitter may provide more than one SCV if they have more than one type of classification for a variant.

Aggregate records (RCV and VCV) have an aggregate classification for as many classification types as there is submitted data. For example, a VCV record may have only a germline classification; it may have only a somatic classification of clinical impact; or it may have three classifications, one germline, one somatic clinical impact, and one oncogenicity.

We anticipate that classifications in ClinVar will continue to evolve to better represent other areas such as pharmacogenomics, functional impact, mitochondrial variants, and diseases of somatic mosaicism.

Classification on ClinVar submitted records (SCV)

Standards for classification terms

ClinVar uses standard terms for classifications recommended by an authoritative source when available. These standards include:

A few other non-standard terms are also used to meet submitter needs for germline variants. We plan to add standard terms for other scenarios (e.g. pharmacogenomic and mitochondrial variants) when they are available.

Options for germline classification

The following table lists the options for germline classification for a submitted record (SCV) in ClinVar and guidance for when each term should be used.

Germline classification Guidance for use in ClinVar SCV records
Benign As recommended by ACMG/AMP for variants classified for Mendelian diseases.
Likely benign As recommended by ACMG/AMP for variants classified for Mendelian diseases.
Uncertain significance As recommended by ACMG/AMP for variants classified for Mendelian diseases.
Likely pathogenic As recommended by ACMG/AMP for variants classified for Mendelian diseases.
Pathogenic As recommended by ACMG/AMP for variants classified for Mendelian diseases.
Likely pathogenic, low penetrance As recommended by ClinGen for variants with decreased penetrance for Mendelian diseases.
Pathogenic, low penetrance As recommended by ClinGen for variants with decreased penetrance for Mendelian diseases.
Uncertain risk allele As recommended by ClinGen for variants with decreased penetrance for Mendelian diseases.
Likely risk allele As recommended by ClinGen for variants with decreased penetrance for Mendelian diseases.
Established risk allele As recommended by ClinGen for variants with decreased penetrance for Mendelian diseases.
drug response A general term for a variant that affects a drug response, not a disease.
association For variants identified in a GWAS study and further classified for disease.
protective For variants that decrease the risk of a disorder, including infections.
Affects For variants that cause a non-disease phenotype, such as lactose intolerance.
conflicting data from submitters Only for submissions from a consortium, where groups within the consortium have conflicting classifications of a variant but provide a single submission to ClinVar. This value was only used for early submissions from one consortium. Currently, we ask that a consortium come to its own consensus on a variant’s classification before submission to ClinVar.
other If ClinVar does not have the appropriate term for your submission, we ask that you submit "other" as the classification and include the appropriate term as "Explanation if classification is other or drug response".

not provided

For submissions without a of classification of the variant. The primary goal of ClinVar is to archive variant classifications, so submissions with a classification of "not provided" are limited to:

  • "literature only" submissions that only report a publication about the variant, without providing a classification
  • "research" submissions that provide functional data (e.g. undetectable protein level) but no classification of the variant for a disease
  • "phenotyping only" submissions from clinics or physicians that provide additional information about individuals with the variant, such as observed phenotypes, but do not provide a classification of the variant
'-' This value may not be submitted. It is used in the file variant_summary.txt.gz in the path  https://ftp.ncbi.nlm.nih.gov/pub/clinvar/tab_delimited/. This file reports  '-' in the ClinicalSignificance column for a variant that was submitted to ClinVar only in combination with another variant (e.g. a submission for classification of a haplotype or a genotype) and was not classified explictly.  In that case, ClinVar has no classification specific to that variant.  To find the record that includes that variant, you can query ClinVar by the AlleleID,e.g. https://www.ncbi.nlm.nih.gov/clinvar/?term=38420[alleleid].

Assertion score

Submitters are encouraged to provide documentation describing the criteria they use to classify variants, referred to as assertion criteria. If the assertion criteria include a point-based scoring system, the final score, or point value, can be submitted as the Assertion score. The ACMG/ClinGen CNV Guidelines, 2019 is an example of a point-based scoring system for variant classification.

Germline classification and mode of inheritance

Submitters should provide a germline classification in the context of a submitted mode of inheritance, when known. Thus a disease-causing variant for a recessive disorder should be reported as Pathogenic, not Benign, even though a single copy will not cause disease.

When a submitter specifies a mode of inheritance, that value is displayed on the variant page in the "Submissions - Germline" table in parentheses in the Conditions column, as in this example.

Options for somatic classification

The following table lists the options for somatic classification for a submitted record (SCV) in ClinVar and guidance for when each term should be used.

Somatic classification Guidance for use in ClinVar SCV records
Tier I - Strong As recommended by AMP/ASCO/CAP for somatic variants classified for their clinical impact.
Tier II – Potential As recommended by AMP/ASCO/CAP for somatic variants classified for their clinical impact.
Tier III – Uncertain significance As recommended by AMP/ASCO/CAP for somatic variants classified for their clinical impact.
Tier IV – Benign/likely benign As recommended by AMP/ASCO/CAP for somatic variants classified for their clinical impact.
Oncogenic As recommended by ClinGen/CGC/VICC for somatic variants classified for oncogenicity.
Likely oncogenic As recommended by ClinGen/CGC/VICC for somatic variants classified for oncogenicity.
Uncertain significance As recommended by ClinGen/CGC/VICC for somatic variants classified for oncogenicity.
Likely benign As recommended by ClinGen/CGC/VICC for somatic variants classified for oncogenicity.
Benign As recommended by ClinGen/CGC/VICC for somatic variants classified for oncogenicity.

ClinVar supports two types of classification for somatic variants:

  • Classification of clinical impact, as described in the AMP/ASCO/CAP guidelines
  • Classification of oncogenicity, as described by the ClinGen/CGC/VICC recommendation

A somatic classification of clinical impact may describe one of three types of assertions: therapeutic, diagnostic, or prognostic.

  • Therapeutic: an assertion of therapeutic impact includes whether the variant predicts sensitivity/response, reduced sensitivity or resistance to a therapy. The drug, class of drugs, or combination of drugs is also provided in the submission.
  • Diagnostic: an assertion of diagnostic impact includes whether the variant supports diagnosis or excludes diagnosis.
  • Prognostic: an assertion of prognostic impact includes whether the variant is associated with a better outcome or a poor outcome.

Source of classifications

The classification that ClinVar represents on a submitted record is not calculated by NCBI. The classification of a variant is provided only by the submitter. The classification on the submitter's record, represented by an accession starting with SCV, is used to calculate conflicts among classifications when

  • all submissions about the same variant are aggregated into a record with an accession starting with VCV
  • all submissions about the same variant and condition are aggregated into a record with an accession starting with RCV

In other words, ClinVar staff do not curate submitted classifications. If you believe a classification is in error, you are invited to submit your own variant classification with supporting evidence so that the conflict will be noted and external curationi groups such as ClinGen can focus on evaluation of all evidence.

There are two exceptions to the statement that ClinVar processes only what is explicitly submitted about classifications:

  • In some early submissions, some submitters provided classification using their own values. In this case, the SCV record reflects the submitted value for the classification, but ClinVar staff worked with the submitter to map the submitted value to one of NCBI's standard values. This standardization is necessary to support calculation of conflicts in classification. Current submissions to ClinVar must use the list of classification terms that ClinVar processes.
  • Data provided by OMIM do not include an explicit classification. When ClinVar processes data from OMIM, we map the disorders or phenotypes associated with each record into allowed values for classification according to the following guidelines provided by OMIM:

Key Word(s) in Title of OMIM Entry or description in OMIM's genemap file Classification
Rules for Assigning Classification Values to OMIM's Allelic Variants
non-disease Affects
named protein variants other, unless curated by NCBI staff to connect to a condition or phenotype
"POLYMORPHISM" Benign
"PROTECTION AGAINST" protective
"QUANTITATIVE TRAIT" association
"RESPONSE" not "SUSCEPTIBILITY" drug response
"SOMATIC" not "RESPONSE" Pathogenic

"SUSCEPTIBILITY TO"
"SUSCEPTIBILITY" followed by a numeral
"MODIFIER OF" not "RESPONSE"

risk factor

Note: For the case of variants in BRCA1 and BRCA2 related to breast cancer, OMIM asserted these should be treated as Pathogenic.
"VARIANT OF UNKNOWN SIGNIFICANCE" Uncertain significance, also reviewed as time permits to determine if there is a disorder for which the variant has an uncertain significance.
contains an identifier from dbSNP Reviewed as time permits to determine if the accompanying text is reporting an association, a polymorphism, or a causative variant.
key title word(s) that do not match any of the above Pathogenic

Classification on ClinVar aggregate records (VCV and RCV)

Overview

ClinVar calculates an aggregate classification for each of the three types of classifications – germline, somatic classification of clinical impact, and oncogenicity. ClinVar aggregates the values of each type of classification provided in submitted records (SCV) by the variant (VCV records) and by the variant/condition combination (RCV records).

Some classifications are given more weight in doing that aggregation, based on the review status of each submitted record represented in the VCV or RCV. Submitted records are used in this order of precedence of review statuses:

  1. practice guideline (4 stars): The classification from the practice guideline record is used as the classification on the VCV and RCV records, no matter what other submitters may have reported.
  2. Reviewed by expert panel (3 stars): The classification from the expert panel record is used as the classification on the VCV and RCV records, no matter what other submitters may have reported.
  3. criteria provided, single submitter (1 star): The classification from all submitted records with this review status is used to calculate the aggregate classification on the VCV and RCV records.
    • For example, the classification on a single SCV record with review status "criteria provided, single submitter" supersedes classifications on multiple SCV records with lower review statuses.
  4. no assertion criteria provided (0 stars): The classification from all submitted records with this review status is used to calculate the aggregate classification on the VCV and RCV records, if there is no record with higher precedence.

When there is a submission from an expert panel or a practice guideline, only the classification from that group is reported as the aggregate classification even if other submissions provide different classifications. The classifications on the SCV records from other submitters are not changed, but they do not contribute to the aggregate classification.

Conflicts in the aggregate classification are calculated for germline and oncogenicity classifications; see the following sections for more details. Conflicts on aggregate records are reported in the XML files, the VCF files, the tab-delimited variant_summary.txt file, and on VCV and RCV web pages

Aggregate germline classification

The classification terms recommended by ACMG/AMP use five levels to describe pathogenicity of germline variants for Mendelian disorders. Five additional terms to classify risk alleles and low-penetrance Mendelian variants were introduced by ClinGen; see Options for classification. A difference in germline classification among submitters within these ten terms only are reported as a conflict using the phrase ‘Conflicting classifications of pathogenicity’.

Other values of germline classification described in Options for classification are not considered in the determination of conflicting classifications. When ClinVar aggregates submissions from groups that provided a standard term not recommended by ACMG/AMP or ClinGen (e.g. drug response), those values are reported after the ACMG/AMP or ClinGen term (see the table below).

RCV records

  • Starting in June 2022, conflicts on RCV records are reported between these levels of pathogenicity:
    • Any pathogenic/risk term vs any uncertain term
    • Any pathogenic/risk term vs any benign term
    • Any uncertain term vs any benign term
  • Starting in May 2018, conflicts on RCV records were reported between three levels of pathogenicity, i.e. Benign or Likely benign vs Uncertain significance vs Pathogenic or Likely pathogenic.
  • Before May 2018, any conflict within the five terms of pathogenicity from ACMG/AMP was reported as a conflict. e.g. Pathogenic and Likely pathogenic were reported as a conflict.

VCV records

  • Starting in June 2022, conflicts on VCV records are reported between these levels of pathogenicity:
    • Any pathogenic/risk term vs any uncertain term
    • Any pathogenic/risk term vs any benign term
    • Any uncertain term vs any benign term
  • Before June 2022, conflicts were reported between three levels of pathogenicity, e.g. Benign or Likely benign vs Uncertain significance vs Pathogenic or Likely pathogenic.

Combination of terms from different submitters Aggregate germline classification
  • Pathogenic
  • Likely pathogenic
  • Pathogenic, low penetrance
  • Likely pathogenic, low penetrance
  • Established risk allele
  • Likely risk allele
 The combination of terms, separated by ‘/’.
e.g. Pathogenic/Likely pathogenic
e.g. Pathogenic/Established risk allele
Uncertain significance AND Uncertain risk allele Uncertain significance/Uncertain risk allele
Benign AND Likely benign Benign/Likely benign
  • Any pathogenic/risk term AND any uncertain term
  • Any pathogenic/risk term AND any benign term
  • Any uncertain term AND any benign term
 Conflicting classifications of pathogenicity.
The conflicting terms and the number of submissions are also provided.
e.g. Pathogenic(1); Uncertain significance(1)
Any single ACMG or ClinGen term AND any other term, e.g. Pathogenic and drug response The combination of terms, separated by ‘;’
e.g. Pathogenic; drug response
Conflicting ACMG or ClinGen terms AND any other term, e.g. Pathogenic and Uncertain significance and drug response Conflicting classifications of pathogenicity; other terms follow separated by ‘;’
e.g. Conflicting classifications of pathogenicity; drug response
The conflicting terms and the number of submissions are also provided.
e.g. Pathogenic(1);Uncertain significance(1)
No ACMG or ClinGen term AND multiple other terms, e.g. drug response and other The combination of terms, separated by ‘;’
e.g. drug response; other
A consortium does not agree on which ACMG classification term is correct Conflicting data from submitters
This value has only been used for early submissions from one consortium. Currently, we ask that a consortium come to its own consensus on a variant’s classification before submission to ClinVar.

Aggregate somatic classification of clinical impact

ClinVar calculates the aggregate somatic classification of clinical impact as the highest tier reported for the variant, for any type of assertion (therapeutic, diagnostic, or prognostic), from SCV records with the highest review status. On the VCV page, a note indicates if other tiers have been submitted too.

Conflicts are not calculated for the aggregate somatic classification of clinical impact. It is expected that ClinVar will receive varying classifications for a variant, for different tumor types and types of assertions. Thus, no conflicts are calculated for clinical impact.

Some examples:

Submitted records for a variant Aggregate somatic classification of clinical impact
  • One SCV with review status “reviewed by expert panel”: Tier II – Potential for therapeutic impact
  • One SCV with review status “criteria provided, single submitter”: Tier I - Strong for therapeutic impact
Tier II – Potential
  • One SCV with review status “criteria provided, single submitter": Tier I – Strong for therapeutic impact
  • One SCV with review status “criteria provided, single submitter”: Tier II – Potential for therapeutic impact
Tier I - Strong
  • One SCV with review status “criteria provided, single submitter”: Tier II – Potential for therapeutic impact
  • One SCV with review status “no assertion criteria provided”: Tier 1 – Strong for prognostic impact
Tier II - Potential

Aggregate somatic classification of oncogenicity

The classification terms recommended by ClinGen/CGC/VICC use five levels to describe oncogenicity of somatic variants for cancer. A difference in the oncogenicity classification among submitters within these five terms are reported as a conflict using the phrase ‘Conflicting classifications of oncogenicity’.

Combination of terms from different submitters Aggregate oncogenicity classification
  • Oncogenic
  • Likely oncogenic
Oncogenic/Likely oncogenic
  • Benign
  • Likely benign
Benign/Likely benign
  • Any oncogenic term AND Uncertain significance
  • Any oncogenic term AND any benign term
  • Uncertain significance AND any benign term
Conflicting classifications of oncogenicity
The conflicting terms and the number of submissions are also provided.
e.g. Oncogenic(1); Uncertain significance(1)

Terminology

Several different terms have been used in ClinVar for the field that represents the relationship between the variant and a condition. These terms include “clinical significance,” “assertion,” “interpretation,” and "classification"; each term was used based on feedback from ClinVar's community of users. There does not appear to be a standard that is used uniformly across all of clinical genetics.

Regardless of the term used, the variant-condition relationship in ClinVar is considered a variant‐level classification, not a patient‐specific interpretation. It may represent the relationship between a variant and Mendelian disease, cancer, or a drug response. As the relationship may be asserted through clinical testing, research, or curation, an “classfication” is not limited to a specific clinical context. PMID 30311387

Prior to 2024, ClinVar had a single field for the clinical significance, or interpretation, of the variant. In the January 29, 2024 release, this field was split into three fields for the three classification types described above – germline classification, somatic classification of clinical impact, and oncogenicity.

Last updated: 2024-02-01T20:57:55Z