KRAS c.34G>C, p.Gly12Arg
NM_033360.2:c.34G>C
COSMIC ID: COSM518
Pathogenic
NM_033360.2:c.34G>C (p.G12R) in KRAS meets one Strong (PS1), three Moderate (PS3, PM1, PM5), and three Supporting (PM2, PP3, PP5) criteria, consistent with a Pathogenic classification under ACMG/AMP and VCEP guidelines.
ACMG/AMP Criteria Applied
PS1
PS3
PM2
PM5
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>C
Protein Change
G12R
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
COSM518
Variant interpretation based on transcript NM_033360.2
Genome Browser
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HGVS InputNM_033360:c.34G>C
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
2 publications
Likely Pathogenic
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
3 Path
1 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
proposed classification - variant undergoing re-assessment, contact laboratory
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 12 of the KRAS protein (p.Gly12Arg). 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. 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. 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. ClinVar contains an entry for this variant (Variation ID: 12579). This variant has not been reported in the literature in individuals affected with KRAS-related conditions. This variant is not present in population databases (gnomAD no frequency).
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratories).
COSMIC ID
COSM518
Recurrence
1642 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
The KRAS G12R variant has been functionally characterized as oncogenic. It is located in the P-loop of the catalytic G-domain of the KRAS protein and has been shown to be activating in colorectal cancer cell lines, as evidenced by increased RAS-GTP levels, downstream pathway activation, and enhanced in vivo tumor growth compared to the wildtype. Additionally, in vitro studies indicate that this variant confers resistance to cetuximab and BRAF inhibitors but remains sensitive to the MEK inhibitor cobimetinib.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.821
0.821
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:
metasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.50
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 exon or multiexon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows: it is a missense change (G12R), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Strong)
According to VCEP guidelines, the rule for PS1 is: "Strong: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in HRAS, KRAS, MRAS, NRAS, RIT1, and RRAS2." The evidence for this variant shows: NM_033360.2:c.34G>C yields the identical amino acid substitution G12R that is established as pathogenic in KRAS. Therefore, this criterion is applied at Strong strength because the variant produces the same amino acid change as a known pathogenic variant.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no information on de novo occurrence or parental testing. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Moderate: Two or more different approved assays demonstrating damaging effect. Modification Type: Disease-specific, Gene-specific, Strength." The evidence for this variant shows: multiple functional assays (increased RAS-GTP levels in vitro, downstream pathway activation, enhanced in vivo tumor growth, drug resistance and sensitivity assays) demonstrate a damaging, activating effect. Therefore, this criterion is applied at Moderate strength.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to controls." The evidence for this variant shows: no germline case‐control data or segregation in multiple unrelated affected individuals. Therefore, this criterion is not applied.
PM1
PM1 (Moderate)
According to VCEP guidelines, the rule for PM1 is: "Moderate: 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]). Not applicable to specific amino acid residues (see PM5). Modification Type: Gene-specific." The evidence for this variant shows: G12 lies within the P-loop (AA 10-17), a known mutational hotspot without benign variation. Therefore, this criterion is applied at Moderate strength.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting: The variant must be absent from controls (gnomAD)." The evidence for this variant shows: absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength.
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: this is not a recessive context and no trans observation. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame indels or stop-loss variants in nonrepeat regions." The evidence for this variant shows: it is a missense change, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines, the rule for PM5 is: "Moderate: 1 [likely] pathogenic residue change at the same codon. Modification Type: Analogous Gene, Disease-specific." The evidence for this variant shows: other pathogenic missense changes (e.g., G12D, G12V, G12C) have been reported at codon 12. Therefore, this criterion is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no information on de novo occurrence. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Cosegregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense is a common disease mechanism." The evidence for this variant shows: KRAS has multiple benign and pathogenic missense variants and overall missense variation is common. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "Supporting: For missense variants, REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism." The evidence for this variant shows: REVEL=0.82 ≥0.7 and multiple in silico tools predict deleterious effect. Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no germline phenotype data specific to KRAS-associated inherited syndrome. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: ClinVar entries from multiple clinical labs classify G12R as Pathogenic/Likely Pathogenic without primary data. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is greater than 5% in a general population database." The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder." The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult for a recessive (homozygous) or dominant (heterozygous) disorder without manifestation of disease." The evidence for this variant shows: no observations in healthy individuals with genotype information. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing." The evidence for this variant shows: functional studies demonstrate a damaging, activating effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "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 standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which primarily truncating variants cause disease." The evidence for this variant shows: KRAS disease mechanism is gain-of-function missense, not truncating. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant dominant disorder or observed in cis with a pathogenic variant." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: it is a single-nucleotide missense change, 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=0.82, predicting deleterious effect. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular diagnosis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign but evidence not available." The evidence for this variant shows: no reputable source classifies it as benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted splice impact and nucleotide not highly conserved." The evidence for this variant shows: it is a missense, not synonymous. Therefore, this criterion is not applied.