KRAS c.34G>T, p.Gly12Cys
NM_033360.2:c.34G>T
COSMIC ID: COSM516
Pathogenic
G12C lies in the critical P-loop domain and is absent from population controls; multiple functional assays confirm gain-of-function, other codon 12 residues are pathogenic, and computational and database sources support pathogenicity. Together this meets three Moderate and four Supporting criteria, consistent with a Likely Pathogenic classification.
ACMG/AMP Criteria Applied
PS3
PM1
PM2
PM5
PP2
PP3
PP5
Genetic Information
Gene & Transcript Details
Gene
KRAS
Transcript
NM_033360.2
Total Exons
6
Strand
Reverse (−)
Reference Sequence
NC_000012.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_033360.4 | Alternative | 6 exons | Reverse |
| NM_033360.3 | Alternative | 6 exons | Reverse |
Variant Details
HGVS Notation
NM_033360.2:c.34G>T
Protein Change
G12C
Location
Exon 2
(Exon 2 of 6)
5'Exon Structure (6 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 12 in gene KRAS
Alternate Identifiers
COSM516
Variant interpretation based on transcript NM_033360.2
Genome Browser
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HGVS InputNM_033360:c.34G>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 249272Alt: 0Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0%, 0/249272 alleles, homozygotes = 0) but does not appear at a higher frequency in any of the selected populations. The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
3 publications
Likely Pathogenic
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
3 Path
2 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (3)
ClinVar contains an entry for this variant (Variation ID: 12578). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 12 of the KRAS protein (p.Gly12Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KRAS-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRAS protein function. Experimental studies have shown that this missense change affects KRAS function (PMID: 16051643). This variant disrupts the p.Gly12 amino acid residue in KRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17704260, 26242988). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Likely pathogenic (2 clinical laboratories).
COSMIC ID
COSM516
Recurrence
5538 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
COSMIC Database Preview
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Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
21750
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (21750 mutations).
PM1 criterion applied.
Related Variants in This Domain
No evidence of other pathogenic variants at position 12 in gene KRAS
Functional Summary
Gain-of-Function
The KRAS G12C variant has been functionally characterized as a gain-of-function mutation. It is known to be oncogenic, leading to increased pathway activation, cell proliferation, colony formation, and in vivo tumor formation compared to the wildtype. This variant has been shown to be sensitive to targeted therapies specifically designed for it, and clinical trials have demonstrated significant patient responses to these therapies.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.853
0.853
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.99
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease.' The evidence for this variant shows: transcript and variant consequence are unknown, so a null effect cannot be assessed. Therefore, this criterion is not applied because variant consequence cannot be determined.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Strong: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows: NM_033360.2:c.34G>T is the only nucleotide change known to produce G12C and there is no alternate nucleotide change resulting in the same amino acid. Therefore, this criterion is not applied because no different nucleotide change producing the same amino acid has been observed.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: 'Very Strong: confirmed de novo in a patient with the disease and no family history; Strong: assumed de novo; Moderate: evidence of de novo without paternity/maternity confirmed.' The evidence for this variant shows: no parental or de novo information is available. Therefore, this criterion is not applied due to lack of de novo data.
PS3
PS3 (Moderate) Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Moderate Strength: Two or more different approved assays.' The evidence for this variant shows: multiple functional studies demonstrate gain-of-function (pathway activation, increased proliferation, colony formation, in vivo tumor formation, and sensitivity to targeted therapies). Therefore, this criterion is applied at Moderate strength because multiple approved assays support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Strong: ≥5 points; Moderate: ≥3 points; Supporting: ≥1 point from case data or statistical evidence.' The evidence for this variant shows: no case‐level or statistical case‐control data have been provided. Therefore, this criterion is not applied due to lack of case-level aggregation.
PM1
PM1 (Moderate)
According to VCEP guidelines, the rule for PM1 is: 'Moderate Strength: Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]).' The evidence for this variant shows: G12C lies within the P-loop (AA 10-17), a mutational hotspot with well-established functional impact. Therefore, this criterion is applied at Moderate strength.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting Strength: The variant must be absent from controls (gnomAD).' The evidence for this variant shows: not observed in gnomAD (0/249272 alleles). Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant.' The evidence for this variant shows: no information on trans‐configuration with another pathogenic variant. Therefore, this criterion is not applied due to lack of trans data.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions in a non-repeat region.' The evidence for this variant shows: the variant is a missense change without alteration of protein length. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines, the rule for PM5 is: 'Moderate Strength: One likely pathogenic residue change at the same codon.' The evidence for this variant shows: multiple other missense changes at codon 12 (e.g., G12D, G12V) are established as pathogenic. Therefore, this criterion is applied at Moderate strength because an analogous residue change at the same codon is pathogenic.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: 'Strong: 2 points; Moderate: 1 point; Supporting: 0.5 points for assumed de novo.' The evidence for this variant shows: no de novo or mosaic information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Strong: ≥7 informative meioses; Moderate: ≥5 meioses; Supporting: ≥3 meioses.' The evidence for this variant shows: no segregation data in families. Therefore, this criterion is not applied.
PP2
PP2 (Supporting)
According to standard ACMG guidelines, the rule for PP2 is: 'Supporting: Missense variant in a gene with low rate of benign missense variants where missense is a common disease mechanism.' The evidence for this variant shows: KRAS has low benign missense variability and gain-of-function missense is the disease mechanism. Therefore, this criterion is applied at Supporting strength.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: 'Supporting Strength: For missense variants, REVEL ≥ 0.7.' The evidence for this variant shows: REVEL score 0.85 exceeds the 0.7 threshold. Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Supporting: Patient phenotype or family history highly specific for a gene.' The evidence for this variant shows: no germline phenotype or specific clinical presentation provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: 'Supporting: Reputable source reports variant as pathogenic but evidence not available for independent evaluation.' The evidence for this variant shows: ClinVar entries from multiple laboratories classify G12C as Pathogenic or Likely Pathogenic. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone: GnomAD filtering allele frequency ≥0.05%.' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Strong: GnomAD filtering allele frequency ≥0.025%.' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Strong: Observed in multiple healthy individuals; Supporting: Observed in any healthy individual.' The evidence for this variant shows: no data from healthy individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'Strong: Well-established functional studies show no damaging effect.' The evidence for this variant shows: functional studies demonstrate a damaging, gain-of-function effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Strong: Lack of segregation in affected members of a family.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP1 is: 'Supporting: Truncating variants in genes where gain-of-function is the disease mechanism; not applicable for missense.' The evidence for this variant shows: the variant is missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Strong/Moderate/Supporting: Observed in trans or cis with a pathogenic variant in recessive conditions.' The evidence for this variant shows: no cis/trans data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'Supporting: In-frame indels in repetitive regions without functional impact.' The evidence for this variant shows: the variant is a missense, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: 'Supporting: For missense variants, REVEL ≤ 0.3.' The evidence for this variant shows: REVEL is 0.85. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Supporting: Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no such information. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Supporting: Reputable source reports variant as benign with no evidence.' The evidence for this variant shows: ClinVar reports pathogenicity, not benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Supporting: Synonymous variant with no impact on splicing and low conservation.' The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.