Name

The Variant Name describes the specific variant being interpreted for clinical utility. Selecting a Variant Name in the Variant list for a Gene will bring up a Variant specific page with a description, aliases, HGVS expressions, ClinVar identifiers, Variant Type(s) and associated Evidence Items.

Understanding Variant Names

The Variant Name concisely describes a defining feature of the variant for rapid and clear identification. The Variant Name should be the most specific description of the variant that the underlying sources allow. However, names can be generalized to categorical variants (also called “bucket” variants) such as Mutation or Exon 11 Mutation, if more granular detail is not provided. Categorical variants often arise during studies that pool larger numbers of patients with unspecified mutations in a given gene or gene region, in order to reach statistical conclusions. Variant Names often follow HGVS-like conventions (e.g. L858R).

Adding New Variant Names

New CIViC Variant Names are entered into the database at the first instance of curation of evidence for the given variant. At the time of entering an Evidence Item for a new variant, the user generates the name by entering it into the Variant Name field, below the Gene Entrez Name field. Unlike Entrez name, which is drawn from a list of predetermined gene names, the variant name is free text written by the curator.

Screenshot of Gene and Variant fields in the Add Evidence form

Figure 1: Screenshot of Gene and Variant fields in the Add Evidence form

Curating Variant Names

When curating the Variant Name field, the most specific Variant Name described by the source should be used (e.g. KRAS G12 or G13 rather than KRAS Exon 2 Mutation). The Variant Name can be very specific [e.g. VHL R176fs (c.528del)], or can refer to a collection of variants fitting a named category (i.e. categorical variants). Examples of categorical variants include KRAS G12 or G13, EGFR Exon 20 Insertion, and PIK3CA Mutation. Categorical variants may be associated with multiple ClinVar entries. The Variant Name field is not limited to genetic events and can include expression or epigenetic alterations such as BRCA1 Underexpression or CDKN2A Promoter Hypermethylation. Other Variant Names, including star-allele nomenclature adopted by the pharmacogenetics field (e.g. DPYD*2A) are also supported. Variant Names can be associated with one or more Variant Types derived from the Sequence Ontology.

General Conventions:

  • Title case should be used.

  • Names and HGVS expressions should follow the HGVS 3’ rule.

  • Protein changes should be written in 1-letter form and exclude the preceding ‘p.’.

  • HGVS for c. and g. nomenclature may be used and should include the preceding ‘c.’ or ‘g.’ to differentiate it from protein nomenclature.

  • Shorthand should be avoided (e.g., use Mutation instead of Mut, Expression instead of Exp, etc.) unless part of HGVS nomenclature (e.g., E746_T751delinsVA).

  • ‘or’ rather than ‘/’ should be used to connect variants (e.g. G12 or G13, not G12/G13).

  • Frameshift Variant Names should use the shorter HGVS-like protein naming style (e.g., P86fs). The longer protein nomenclature, which includes predicted downstream protein consequences can be included as an alias (e.g., P86Afs*46).

  • Somatic variants are not typically described at the genome or transcript level in publications. Protein-effect level descriptions are appropriate for most somatic variants.

  • Categorical variants should be singular and exclude the gene name (e.g., Fusion, Rearrangement, Mutation, Frameshift rather than ‘ALK Fusions’).

  • Splice variants should not use IVS nomenclature.

The table below includes an extensive set of example variants for many of the common variant types supported in CIViC. When curating a new variant, curators should refer to these examples and follow the established conventions wherever possible. The {sequence variant} root concept of Sequence Ontology is implied for Variant Type when it’s not otherwise specified.

Variant name

Gene

Variant type

Application and Notes

V600E

BRAF

Missense Variant

A specific amino acid change. Variant Name encapsulates all the nucleotide changes that could have produced it. Somatic variants are not typically described at the genome or transcript level in publications.

S65W (c.194C>G)

VHL

Missense Variant

A specific amino acid change where the precise nucleotide change is provided or ascertainable. Protein change p. notation is implied, other HGVS notation (e.g. ‘g.’ or ‘c.’) used when applicable. This degree of resolution is typically used for germline variants.

E709A and G719C

EGFR

Missense Variant

Multiple concomitant missense variants in the same gene (e.g. double mutants). Should not be used when patients with different mutations in the same gene are pooled and analyzed.

V600E or V600K

BRAF

Missense Variant, Copy Number Gain {sequence feature}

Different specific missense variants in the same gene but different patients pooled together. The shorthand V600E/K should not be used.

(V600E or V600K) and Amplification

BRAF

Missense Variant, Copy Number Gain {sequence feature}

Complex combination between two different types of variants in the same gene (e.g. missense and copy number gain). Boolean order of operations and parentheses should be used when needed.

V600

BRAF

Protein Altering Variant

Categorical variant involving a single amino acid position with multiple possible changes.

Non-V600

BRAF

Protein Altering Variant

Categorical variant excluding a common hotspot. This variant describes all BRAF mutations that are not at the V600 locus.

*214C (c.641_642insC)

VHL

Stop Lost

Use * rather than Ter to indicate a stop codon.

D770_N771insNPG

EGFR

Conservative In-frame Insertion

In-frame insertion of one or more amino acids.

V560del

KIT

Conservative In-frame Deletion

In-frame deletion of one or more amino acids.

E746_T751delinsVA

EGFR

Delins {sequence feature}

Replacement of one or more amino acids with one or more amino acids.

Y772_A775dup

ERBB2

In-frame Insertion

In-frame duplication of one or more amino acids.

P59fs (c.173_174insT)

VHL

Plus 1 Frameshift Variant, Frameshift Truncation

Insertion of one or more nucleotides into DNA causing a frameshift.

E189fs (c.565del)

VHL

Minus 1 Frameshift Variant, Frameshift Truncation

Deletion of one or more nucleotides causing a frameshift.

I206fs (c.615delinsAA)

VHL

Plus 1 Frameshift Variant, Frameshift Elongation

Replacement of one or more nucleotides with one or more nucleotides causing a frameshift.

A149fs (c.444dup)

VHL

Plus 1 Frameshift Variant, Frameshift Truncation

Duplication of one or more nucleotides inserted directly 3’ of the original copy of that sequence.

W288fs

VHL

Frameshift Variant

All frameshifts originating at the codon containing the designated locus. Used when the specific DNA change resulting in the frameshift is unknown, thus the first amino acid to change is unknown.

Exon 9 Frameshift

CALR

Frameshift Variant

All frameshifts originating in this exon.

Frameshift

MRE11

Frameshift Variant

All frameshifts within a gene.

Exon 11 Mutation

KIT

Coding Sequence Variant

Mutations within specific transcriptional boundaries.

Exon 14 Skipping Mutation

MET

Exon Loss Variant

All mutations causing specific transcriptional consequences.

DNA Binding Domain Mutation

TP53

DNA Binding Site {sequence feature}

Mutations within specific functional boundaries.

Mutation

PIK3CA

Transcript Variant

All genetic variants within a gene. Widest categorical variant name for genetic variants.

EML4-ALK

ALK

Transcript Fusion

Specific gene fusion: GENEA-GENEB. Fusions should be named 5’->3’ where GENEA occurs at the 5’ end of the fusion transcript.

EML4-ALK e6-e20

ALK

Transcript Fusion

Fusion with known specific exon boundaries; specific fusion isoforms.

BCR-ABL T315I

ABL1

Transcript Fusion, Missense Variant

Complex genotype describing a concurrent fusion variant and a missense variant.

Fusion

ALK

Transcript Fusion

Fusion with an unknown partner (common for fusions detected by methods like FISH).

Rearrangement

MLL

Structural Variant

A change in the genetic structure wherein a fusion protein is not necessarily implied to have been created (e.g. translocations, genetic fusions with a regulatory region).

FLT3-ITD

FLT3

In-frame Insertion

Imprecise internal tandem duplications (insertion) with shared consequences.

Exon 1-2 Deletion

VHL

Deletion {sequence feature}

Deletion of specific regions of a gene.

Partial Deletion

VHL

Deletion {sequence feature}

All partial deletions where boundaries are not specified. When the size of the deletion is known but the specific exons are not, “Partial deletion of 0.7 Kb” can be included in the Evidence Statement, but not the Variant Name.

Deletion

VHL

Deletion {sequence feature}

Presumed deletion of the whole gene.

Underexpression

ATRX

N/A

Reduced or eliminated expression of protein or mRNA products, as detected by assays such as Western blots, RT PCR, IHC. Do not use if the causal genomic alteration is known; the alteration would be the variant name.

Loss

ARID1A

N/A

Broadest categorical (bucket) variant in CIViC, to be used when the source describes a mix of genetic (e.g. Deletion), expression (e.g. Underexpression), and deleterious mutation events, or does not clarify how gene loss was ascertained. Loss can be used at the Assertion level to combine Underexpression and deleterious genetic variants.

Amplification

PIK3CA

Transcript Amplification

The number of gene copies is greater than two.

Overexpression

ERBB2

N/A

Increased expression of protein or mRNA products, as detected by assays such as Western blots, RT PCR, IHC. Do not use if the causal genomic alteration is known; the alteration would be the variant name.

Splice Site (c.340+1G>A)

VHL

Splice Donor Variant

A splice variant that changes the 2 base pair region at the 5’ end of an intron.

Splice Site (c.341-2A>C)

VHL

Splice Acceptor Variant

A splice variant that changes the 2 base pair region at the 3’ end of an intron.

Splice Region (c.463+3A>G)

VHL

Splice Donor Region Variant

Splice region within 3-8 bases of the intron.

Splice Region (c.464-4C>T)

VHL

Splice Region Variant

Splice region within 3-8 bases of the intron.

Promoter Hypermethylation

CDKN2A

N/A

Epigenetic modification.

S473 Phosphorylation

AKT1

N/A

Describe the specific phosphorylated residue(s), if known, or the whole gene if >2 residues or unknown residues were phosphorylated.

rs3814960

CDKN2A

UTR Variant

rsIDs can be used when easily understandable protein- or splice- altering p. or c. notations are not available.

DPYD*2A Homozygosity

DPYD

Splice Donor Variant

Pharmacogenomic nomenclature (can be any applicable variant type).

p16 Expression

CDKN2A

N/A

Use when distinct proteins (e.g. p16 vs. INK4) are transcribed from the same locus.