Variant classification summary

NM_033360.3:c.35G>T

KRAS · NP_203524.1:p.(Gly12Val) · NM_033360.3

GRCh37: chr12:25398284 C>A · GRCh38: chr12:25245350 C>A

Gene: KRAS Transcript: NM_033360.3

Final call

VUS

PM1 moderate PP3 supporting PS3 moderate

Variant details

Gene

KRAS

Transcript

NM_033360.3

Protein

NP_203524.1:p.(Gly12Val)

gnomAD AF

6.200143099302732e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 (Moderate): VCEP-approved functional assays (PMID 20949621) show p.Gly12Val locks RAS in its active GTP-bound state and elevates MEK/ERK signaling.

2

PM1 (Moderate): Gly12 falls within the VCEP-defined P-loop functional domain (amino acids 10-17).

3

PP3 (Supporting): REVEL score 0.91 exceeds the VCEP-specified >=0.7 threshold for missense variants.

4

Synthesis: with one Moderate and two Supporting criteria, no VCEP combination rule for Pathogenic or Likely Pathogenic is met, and the variant is classified as Uncertain Significance (VUS).

Final determination: No Pathogenic/LP rule in the KRAS RASopathy VCEP v2.3 table is satisfied by PM1(Moderate)+PP3(Supporting)+PS3(Moderate) since it lacks a Very Strong/Strong-tier criterion and falls short of the Moderate/Supporting count thresholds, so the variant remains 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: this is a missense substitution (p.Gly12Val), not a null variant, and the KRAS RASopathy VCEP excludes PVS1.	cspec
PS1	N/A	Not applicable: c.35G>T is itself the canonical pathogenic encoding of p.Gly12Val, leaving no alternate nucleotide change as a comparator.	cspec clinvar
PS2	Not assessed	Not assessed: no parental testing results, maternity/paternity confirmation, or confirmed de novo observation were available.	cspec
PS3	Met	Met (Moderate): VCEP-approved assays (PMID 20949621) show p.G12V locks RAS in its active state with elevated MEK/ERK signaling, covering two approved assay categories.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:20949621
PS4	Not assessed	Not assessed: the only supporting report (1 of 65 sebaceous nevi) is a somatic cohort, not a germline case-control study.	cspec PMID:22683711
PM1	Met	Met (Moderate): Gly12 falls within the VCEP-defined P-loop functional domain (amino acids 10-17).	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Not met	Not met: gnomAD v4.1 reports one allele (AF 6.2e-07), so the variant is not absent as the VCEP rule requires.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: the KRAS RASopathy VCEP v2.3 explicitly excludes PM3.	cspec
PM4	Not met	Not met: as a single-nucleotide missense substitution, it does not alter protein length as PM4 requires.	cspec
PM5	Not assessed	Not assessed: no verified, individually cited alternate pathogenic codon-12 substitutions (e.g., G12D, G12C) were available to count.	pm5_candidates cspec
PM6	Not assessed	Not assessed: no parental genotypes or proband phenotype supporting an assumed de novo occurrence were available.	cspec
PP1	Not assessed	Not assessed: no affected relatives, pedigree, or segregation results were reported.	cspec
PP2	N/A	Not applicable: the KRAS RASopathy VCEP v2.3 explicitly excludes PP2.	cspec
PP3	Met	Met (Supporting): REVEL score 0.91 exceeds the VCEP's >=0.7 threshold for missense variants.	cspec revel
PP4	N/A	Not applicable: the KRAS RASopathy VCEP v2.3 explicitly excludes PP4.	cspec
PP5	N/A	Not applicable: the VCEP excludes PP5, and the ClinVar record lacks an expert-panel submission.	cspec clinvar
BA1	Not met	Not met: highest gnomAD allele frequency is 0.000062%, far below the 0.05% BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: highest population allele frequency is 0.000085%, below the 0.025% BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no documented healthy adult carrier with adequate phenotype and penetrance information was available.	cspec gnomad_v4
BS3	N/A	Not applicable: the VCEP excludes BS3, and functional assays show gain-of-function rather than normal behavior.	cspec
BS4	Not assessed	Not assessed: no affected family members with documented absence of the variant or informative non-segregating meiosis were reported.	cspec
BP1	N/A	Not applicable: BP1 is restricted to truncating variants, and this is a missense substitution.	cspec
BP2	Not assessed	Not assessed: no alternative molecular cause, second pathogenic KRAS variant, or phase data were documented.	cspec
BP3	N/A	Not applicable: the VCEP excludes BP3, and this is a missense substitution, not an in-frame indel.	cspec
BP4	Not met	Not met: REVEL 0.91 is well above the VCEP's <=0.3 BP4 threshold.	cspec revel
BP5	Not assessed	Not assessed: no evidence of an alternative molecular explanation for the phenotype was available.	cspec clinvar
BP6	N/A	Not applicable: the VCEP excludes BP6, and no benign expert-panel classification exists for this variant.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants, and this change is missense (p.Gly12Val).	cspec

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