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LYFE SCIENCES
Project: HERA
NM_033360.2:c.34G>C
p.Gly12Arg  ·  KRAS
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

oncokb ↗ PMID:23455880 ↗ PMID:26037647 ↗ PMID:32792368 ↗
4

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).

cspec ↗ spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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).
gnomAD v4.1Absent from gnomAD v4.1.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratory).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Oncogenic
OncoKB classifies this variant as Oncogenic; biological effect: Gain-of-function.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55497582, n = 1720 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueG12
Hotspots ↗