Variant classification summary

NM_004985.5:c.34G>T

KRAS · NP_004976.2:p.(Gly12Cys) · NM_004985.5

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

Gene: KRAS Transcript: NM_004985.5

Final call

Likely Pathogenic

PS1 strong PS3 supporting PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

KRAS

Transcript

NM_004985.5

Protein

NP_004976.2:p.(Gly12Cys)

gnomAD AF

0.0 (v2.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS1 strong: the exact KRAS p.G12C amino-acid change is established as pathogenic.

2

PM1 moderate: residue 12 lies in the approved P-loop domain (amino acids 10-17).

3

PS3 supporting: KRAS-G12C increased GTP-bound KRAS in a RAF1-RBD activation assay.

4

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1 controls.

5

PP3 supporting: REVEL 0.853 exceeds the VCEP cutoff of 0.7.

Final determination: Under KRAS VCEP Rule11, one strong pathogenic criterion plus one moderate pathogenic criterion yields Likely Pathogenic; PS1 strong and PM1 moderate satisfy this rule.

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: the VCEP marks PVS1 not applicable, and c.34G>T is a missense p.(Gly12Cys) substitution rather than a loss-of-function variant.	cspec pvs1_variant_assessment
PS1	Met	Met: ClinVar variation 12578 records the exact KRAS p.G12C change as Pathogenic with three clinical laboratories and no conflicts.	cspec clinvar
PS2	Not assessed	Not assessed: no confirmed de novo proband, parental testing, parental relationships, or qualifying phenotype information is documented for assigning PS2 points.	cspec
PS3	Met	Met at Supporting: KRAS-G12C increased GTP-bound KRAS up to approximately 2-fold in a RAF1-RBD activation assay, while the VCEP permits unlisted assays only at Supporting strength.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:25705018
PS4	Not assessed	Not assessed: no RASopathy case-control counts or VCEP PS4 point score are available; the 25/106 tumor observation is not a RASopathy cohort.	cspec PMID:11745231
PM1	Met	Met at Moderate: residue 12 lies within the VCEP-approved P-loop domain spanning amino acids 10-17.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Met	Met at supporting: no alternate allele was observed in gnomAD v2.1 (0/249,272) and the variant was absent from gnomAD v4.1.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the KRAS VCEP Version 2.3 specification explicitly marks PM3 as not applicable.	cspec
PM4	N/A	Not applicable: c.34G>T changes Gly12 to Cys without altering protein length, so the VCEP PM4 rule is not triggered.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: no qualifying [likely] pathogenic alternate residue at codon 12 was established, and comparator retrieval ended with an HTTP 429 error.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no presumed de novo occurrence or parental-testing evidence is documented for assigning PM6's 2-, 1-, or 0.5-point levels.	cspec
PP1	Not assessed	Not assessed: zero informative meioses are documented, so the VCEP thresholds of 3, 5, or 7 meioses cannot be evaluated.	cspec
PP2	N/A	Not applicable: the KRAS VCEP excludes PP2 because the gene's missense z score is below 3.09 in gnomAD.	cspec
PP3	Met	Met: REVEL 0.853 meets the VCEP PP3 missense threshold of ≥0.7.	cspec revel
PP4	N/A	Not applicable: the KRAS VCEP explicitly directs phenotype-specific evidence to PS4 instead of PP4.	cspec
PP5	N/A	Not applicable: the KRAS VCEP prohibits PP5 use, regardless of ClinVar or OncoKB pathogenicity labels.	cspec clinvar oncokb
BA1	Not met	Not met: gnomAD filtering allele frequency is 0% (0/249,272 alleles), below the VCEP's ≥0.05% BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD filtering allele frequency is 0% (0/249,272 alleles), below the VCEP's ≥0.025% BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy adult homozygote or heterozygote observation with the VCEP-required point score is available.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the KRAS Version 2.3 CSPEC explicitly marks BS3 Not Applicable, and the VCEP assay table assigns BS3_NA to listed functional assays.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no informative non-segregation meiosis or tested unaffected relative lacking the variant is documented.	cspec
BP1	N/A	Not applicable: BP1 is limited to truncating variant types, whereas NM_004985.5:c.34G>T is missense p.Gly12Cys.	cspec
BP2	Not assessed	Not assessed: no documented cis/trans or other allelic observation supplies the VCEP-required BP2 point value.	cspec
BP3	N/A	Not applicable: the VCEP marks BP3 not applicable, and c.34G>T is a missense substitution rather than an in-frame indel in a repeat region.	cspec pvs1_variant_assessment
BP4	Not met	Not met: REVEL 0.853 exceeds the VCEP BP4 missense threshold of ≤0.3.	cspec revel
BP5	Not assessed	Not assessed: no alternative causative variant or VCEP BP5 point total is available to compare with the ≥(-1), ≥(-2), or ≥(-4) thresholds.	cspec
BP6	N/A	Not applicable: the KRAS VCEP prohibits BP6 use, regardless of any reputable-source benign report.	cspec
BP7	N/A	Not applicable: BP7 is limited to synonymous, qualifying intronic, or non-coding variants, whereas this variant is missense.	cspec

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