Variant classification summary

NM_033360.3:c.34G>T

KRAS · NP_203524.1:p.(Gly12Cys) · NM_033360.3

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

Gene: KRAS Transcript: NM_033360.3

Final call

VUS

PS3 supporting PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

KRAS

Transcript

NM_033360.3

Protein

NP_203524.1:p.(Gly12Cys)

gnomAD AF

0.0 (v2.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: one approved functional assay showed increased KRAS activation.

2

PM1 moderate: p.Gly12Cys lies in the approved P-loop domain spanning residues 10–17.

3

PM2 supporting: the variant is absent from gnomAD.

4

PP3 supporting: REVEL 0.853 exceeds the KRAS missense threshold of 0.7.

Final determination: Under the KRAS Version 2.3 criteria-combination framework, one moderate criterion plus three supporting criteria does not match a Pathogenic, Likely Pathogenic, Benign, or Likely Benign rule, so the call is VUS.

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
PVS1	N/A	Not applicable: c.34G>T is a missense change producing p.(Gly12Cys), not a predicted loss-of-function or NMD-triggering variant.	pvs1_variant_assessment pvs1_gene_context final_classification_framework
PS1	Not assessed	Not assessed: available reports document p.Gly12Cys, but no qualifying alternate-nucleotide pathogenic comparator for the same amino-acid change is established.	vcep_alignment_with_pm1_domains_pptx PMID:15696205 PMID:25705018
PS2	Not assessed	Not assessed: no documented proband, confirmed parentage, parental testing, or de novo observation is available for this variant.	final_classification_framework
PS3	Met	Met at Supporting: one approved RAS-activation assay showed KRAS-G12C increased GTP-bound KRAS by up to approximately twofold versus controls.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:25705018 PMID:16051643 PMID:24256730 PMID:26841430
PS4	Not met	Not met: two exact p.G12C tumor observations lack the KRAS VCEP's required germline RASopathy case-control enrichment and documented PS4 point score.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:11745231 PMID:15696205
PM1	Met	Met, Moderate: KRAS p.Gly12Cys affects residue 12, within the VCEP-approved P-loop domain spanning amino acids 10-17.	vcep_alignment_with_pm1_domains_pptx
PM2	Met	Met at Supporting: the variant is absent from gnomAD v4.1 and has frequency 0 in 249,272 gnomAD v2.1 exome alleles.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the KRAS Version 2.3 framework explicitly designates PM3 as not applicable for this autosomal-dominant RASopathy context.	final_classification_framework
PM4	N/A	Not applicable: p.(Gly12Cys) changes one amino acid but causes no protein-length change, the required PM4 consequence.	final_classification_framework pvs1_variant_assessment
PM5	Not assessed	Not assessed: no qualifying alternate pathogenic codon-12 residue change was established, and the comparator search reported zero same-residue candidates after a retrieval-rate failure.	pm5_candidates vcep_alignment_with_pm1_domains_pptx PMID:11745231 PMID:25705018
PM6	Not assessed	Not assessed: no presumed de novo occurrence in an affected proband without parental testing is documented for this variant.	final_classification_framework
PP1	Not assessed	Not assessed: zero informative meioses or phenotype-concordant affected relatives are documented for this variant.	final_classification_framework
PP2	N/A	Not applicable: the governing KRAS VCEP explicitly excludes PP2 for this gene-specific framework.	vcep_alignment_with_pm1_domains_pptx
PP3	Met	Met, supporting: REVEL 0.853 exceeds the KRAS VCEP PP3 supporting threshold of 0.7 for missense variants.	final_classification_framework revel
PP4	N/A	Not applicable: the governing KRAS VCEP explicitly designates PP4 as not applicable.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PP5	N/A	Not applicable: PP5 is excluded by the KRAS VCEP and ClinVar shows zero exact-variant expert-panel submissions.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies clinvar
BA1	Not met	Not met: gnomAD allele frequency is 0 (0/249,272 alleles), below the KRAS VCEP BA1 threshold of 0.05%.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD allele frequency is 0 (0/249,272 alleles), below the KRAS VCEP BS1 threshold of 0.025%.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD reports 0 homozygotes, so there is no observation of this variant in healthy adults for the BS2 rule.	gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the KRAS VCEP Version 2.3 framework explicitly designates BS3 as not applicable.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no informative unaffected relative or documented non-segregation observation is available for this variant.	final_classification_framework
BP1	N/A	Not applicable: BP1 is restricted to qualifying truncating variants, whereas this variant is the missense substitution p.Gly12Cys.	vcep_alignment_with_pm1_domains_pptx
BP2	Not assessed	Not assessed: no affected-proband observation documents a second pathogenic variant or its phase in cis or trans with KRAS p.Gly12Cys.	final_classification_framework PMID:11745231 PMID:15696205 PMID:16051643
BP3	N/A	Not applicable: c.34G>T is a codon-12 missense substitution, not an in-frame insertion or deletion in a repetitive region.	final_classification_framework pvs1_variant_assessment
BP4	Not met	Not met: REVEL 0.853 is above the KRAS VCEP BP4 supporting threshold of <=0.3 for missense variants.	final_classification_framework revel
BP5	Not assessed	Not assessed: the KRAS BP5 point score is unavailable, so its Supporting rule point score >= (-1) cannot be evaluated.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BP6	N/A	Not applicable: BP6 is excluded by the KRAS VCEP and no exact-variant ClinVar expert-panel benign classification exists.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies clinvar
BP7	N/A	Not applicable: c.34G>T is missense, p.Gly12Cys, whereas BP7 applies only to synonymous variants.	final_classification_framework

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