The KRAS c.34G>C (p.Gly12Arg, p.G12R) variant has been observed in somatic cancers in COSMIC (COSV55497582; n=1720) and has been reported in ClinVar with pathogenic and likely pathogenic clinical submissions.1 This variant is absent from population controls, with 0/249272 alleles in gnomAD v2.1 and no observation in gnomAD v4.1, which supports PM2 and argues against BA1 and BS1.2 Available functional evidence is consistent with an activating KRAS effect, and OncoKB classifies this variant as oncogenic with gain-of-function, but the curated RASopathy VCEP materials did not provide sufficient approved variant-specific assay evidence to apply PS3.3 This missense change affects codon 12 within the KRAS P-loop domain, and computational data are consistent with a damaging missense effect, with REVEL 0.821 and no predicted splice disruption by SpliceAI (maximum delta score 0.00).4
Final classification
Likely Pathogenic
PM5PM1PM2PP3
KRAS
c.34G>C
p.Gly12Arg
This variant
The KRAS c.34G>C (p.Gly12Arg, p.G12R) variant has been observed in somatic cancers in COSMIC (COSV55497582; n=1720) and has been reported in ClinVar with pathogenic and likely pathogenic clinical submissions.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 criteria-combination framework; Rule14 applies.
Classification rationale
PM5PM1PM2PP3
Likely Pathogenic
KRAS c.34G>C
PM5 + PM1 + PM2 + PP3
→
Likely Pathogenic
3
oncokb ↗vcep_s_v_i___r_a_s_o_p_a_t_h_y___v_c_e_p___v_2___a_p_p_r_o_v_e_d___f_u_n_c_t_i_o_n_a_l___s_t_u_d_i_e_sPMID:23455880 ↗PMID:26037647 ↗PMID:32792368 ↗
4
cspec ↗spliceai ↗vcep_a_l_i_g_n_m_e_n_t___w_i_t_h___p_m_1___d_o_m_a_i_n_s___p_p_t_x
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_033360.2 · variants mapped to exon structure
KRAS
NM_033360.2
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 13 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
PM1
moderate
review
Pathogenic
This variant affects codon 12 within the KRAS P-loop functional domain, which lies in the VCEP-defined PM1 region spanning amino acids 10 to 17, supporting PM1 at a moderate strength.
p.(Gly12Arg) affects amino acid 12.KRAS P-loop domain is defined as amino acids 10-17 in the VCEP PM1 materials.
PM2
supporting
review
Pathogenic
This variant is absent from population controls in gnomAD, with 0/249272 alleles in gnomAD v2.1 and no observation in gnomAD v4.1, meeting the KRAS VCEP PM2_Supporting rule.
gnomAD v2.1: 0/249272 allelesgnomAD v4.1: absent
PM5
moderate
review
Pathogenic
This missense variant affects codon 12, where other pathogenic missense substitutions have already been established within the RASopathy VCEP framework, so PM5 is met at a moderate strength.
Codon 12 is an established pathogenic residue under the KRAS/RASopathy specification.The VCEP functional-study table lists pathogenic same-codon or analogous codon-12 control substitutions in RAS genes.
PP3
supporting
review
Pathogenic
Available computational evidence supports a damaging missense effect because the REVEL score is 0.821, which is above the KRAS VCEP PP3 threshold of 0.7; SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.
REVEL score 0.821SpliceAI max delta score 0.00
Assessed · not applied
· 4 not met · 9 not assessed
Pathogenic
PS1
No evidence was identified showing the same amino acid change established as pathogenic from a different nucleotide change, so PS1 could not be assessed.
PS2
No confirmed de novo occurrence data were identified, so PS2 could not be assessed.
PS3
Available functional data support an activating effect in cancer systems, but no approved RASopathy VCEP functional assay evidence sufficient to apply PS3 for this specific variant was identified from the curated materials.
PS4
This variant has been observed in somatic cancers and is reported in ClinVar, but no germline RASopathy case-count or point-based evidence was identified to meet the KRAS VCEP PS4 requirements.
PM6
No assumed de novo data were identified, so PM6 could not be assessed.
PP1
No segregation data were identified, so PP1 could not be assessed.
Benign
BA1
Population frequency is below the BA1 threshold.
BS1
Population frequency is below the BS1 threshold.
BS2
No data were identified showing this variant in an unaffected individual under the phenotypic specifications required for BS2, so BS2 could not be assessed.
BS4
No nonsegregation data were identified, so BS4 could not be assessed.
BP2
No data were identified showing this variant in cis or trans with another pathogenic RASopathy variant, so BP2 could not be assessed.
BP4
Available computational evidence does not support BP4 because the REVEL score is 0.821, which is above the benign BP4 threshold of 0.3.
BP5
No alternative molecular explanation for the phenotype in another gene was identified, so BP5 could not be assessed.
N/A · 11
PVS1 · PM3 · PM4 · PP2 · PP4 · PP5 · BS3 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/249272 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16042 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / 249,272
0 hom
0 hom
Not observed in any ancestry group.
+ 8 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Oncogenic
OncoKB classifies this variant as Oncogenic; biological effect: Gain-of-function.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55497582, n = 1720 times).
Hotspots
This variant lies in a statistically significant hotspot.
Sources & reference links