NM_033360.2:c.34G>C

KRAS · NP_203524.1:p.(Gly12Arg) · NM_033360.2

GRCh37: chr12:25398285 C>G · GRCh38: chr12:25245351 C>G

Gene: KRAS Transcript: NM_033360.2

Final call

Likely Pathogenic

PM5_Moderate PM1_Moderate PM2_Supporting PP3_Supporting

Variant details

Gene

KRAS

Transcript

NM_033360.2

Protein

NP_203524.1:p.(Gly12Arg)

gnomAD AF

ClinVar

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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).

Final determination: Rule14 in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Pathogenic.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
BP7	N/A	This is a missense variant, not a synonymous, intronic, or non-coding change, so BP7 does not apply.	cspec
PM5	Met	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.	cspec 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_s
BP5	Not assessed	No alternative molecular explanation for the phenotype in another gene was identified, so BP5 could not be assessed.
BP3	N/A	BP3 is not applicable in this KRAS RASopathy framework because no relevant benign repetitive region is defined for this gene.	cspec
PP1	Not assessed	No segregation data were identified, so PP1 could not be assessed.
BS1	Not met	Population frequency is below the BS1 threshold. The variant was seen 0/249272 alleles in gnomAD v2.1 (0.00000%) and was absent from gnomAD v4.1, which is below the KRAS BS1 threshold of 0.025%.	cspec gnomad_v2 gnomad_v4
PP5	N/A	PP5 is not used in this RASopathy VCEP framework.	cspec
BP1	N/A	This is a missense variant, whereas BP1 in this framework is reserved for truncating variants in genes where gain-of-function missense changes are the primary disease mechanism.	cspec
BP2	Not assessed	No data were identified showing this variant in cis or trans with another pathogenic RASopathy variant, so BP2 could not be assessed.
BA1	Not met	Population frequency is below the BA1 threshold. The variant was seen 0/249272 alleles in gnomAD v2.1 (0.00000%) and was absent from gnomAD v4.1, which is below the KRAS BA1 threshold of 0.05%.	cspec gnomad_v2 gnomad_v4
PS3	Not assessed	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.	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_s PMID:23455880 PMID:26037647 PMID:32792368
PM4	N/A	This is not an in-frame insertion, in-frame deletion, or stop-loss variant, so PM4 does not apply.	cspec
BS3	N/A	BS3 is not applicable in this KRAS RASopathy framework.	cspec
PM1	Met	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.	cspec 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
BS2	Not assessed	No data were identified showing this variant in an unaffected individual under the phenotypic specifications required for BS2, so BS2 could not be assessed.
PP2	N/A	PP2 is not applicable in this KRAS RASopathy framework.	cspec
PM6	Not assessed	No assumed de novo data were identified, so PM6 could not be assessed.
BS4	Not assessed	No nonsegregation data were identified, so BS4 could not be assessed.
PS2	Not assessed	No confirmed de novo occurrence data were identified, so PS2 could not be assessed.
PS4	Not met	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.	cspec clinvar
PVS1	N/A	This missense variant is not a null variant, and PVS1 is not applicable in the KRAS RASopathy specification for this change.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No evidence was identified showing the same amino acid change established as pathogenic from a different nucleotide change, so PS1 could not be assessed.	cspec
PM3	N/A	PM3 is not applicable in this KRAS RASopathy framework.	cspec
PP4	N/A	PP4 is not applicable in this KRAS RASopathy framework.	cspec
PM2	Met	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.	cspec gnomad_v2 gnomad_v4
BP4	Not met	Available computational evidence does not support BP4 because the REVEL score is 0.821, which is above the benign BP4 threshold of 0.3.	cspec
PP3	Met	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.	cspec spliceai
BP6	N/A	BP6 is not used in this KRAS RASopathy framework.	cspec

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