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 aliases, HGVS expressions, ClinVar identifiers, Variant Type(s) and Molecular Profiles.

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 Molecular Profile involving the given Variant. At the time of entering an Evidence Item for a new Molecular Profile, the user generates the Variant and 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.

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.