The variant NM_033360.3:c.460G>A (p.Asp154Asn) is located at codon 154 within the SAK domain (amino acids 145–156), a critical functional domain defined by the ClinGen RASopathy VCEP v2.3.0, meeting PM1 at moderate strength.1 Multiple in silico predictors support a benign impact: REVEL score 0.19 (≤0.3, meeting VCEP BP4 at supporting benign strength), BayesDel score −0.339, and SpliceAI max delta 0.10 (no predicted splicing impact).2 The variant is present in gnomAD v4.1 at an extremely low frequency (2/1,610,578 alleles; AF=1.24×10⁻⁶) and is absent from gnomAD v2.1 and gnomAD-Canada. It is absent from ClinVar. COSMIC reports one somatic occurrence (COSV55736852).3 No variant-specific functional data, de novo observations, segregation data, case-control studies, or published literature referencing this exact variant were identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect.'4 With one moderate pathogenic criterion (PM1) and one supporting benign criterion (BP4), the evidence is balanced and does not meet any VCEP classification rule for pathogenic, likely pathogenic, likely benign, or benign. This variant is classified as a Variant of Uncertain Significance (VUS) under the ClinGen RASopathy VCEP v2.3.0 framework.5
KRAS
Final classification
VUS
KRAS c.460G>A · p.Asp154Asn
KRAS
The variant NM_033360.3:c.460G>A (p.Asp154Asn) is located at codon 154 within the SAK domain (amino acids 145–156), a critical functional domain defined by the ClinGen RASopathy VCEP v2.3.0, meeting PM1 at moderate strength.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PM1 moderate, BP4 supporting benign; no rule matched the adjudicated criteria.
Classification rationale
PM1
BP4
VUS
KRAS c.460G>A
PM1 + BP4
→
VUS
Gene diagram
· NM_033360.3 · variants mapped to exon structure
KRAS
NM_033360.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 15 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
moderate
Pathogenic
The variant is located at codon 154 which falls within the SAK domain (amino acids 145–156), a critical and well-established functional domain specified by the ClinGen RASopathy VCEP v2.3.0 for PM1 application at moderate strength.
VCEP-defined SAK domain spans AA 145-156variant p.Asp154Asn is at position 154 within this domain
✓
BP4
supporting
Benign
The REVEL score is 0.19, which is ≤0.3, meeting the VCEP BP4 threshold for a supporting benign criterion. BayesDel score (-0.339) and SpliceAI (max delta 0.10) also support a benign impact.
REVEL=0.19 (≤0.3 VCEP BP4 threshold)BayesDel=-0.339SpliceAI max delta=0.10
Assessed · not applied
Pathogenic
PS1
No previously established pathogenic variant with the same amino acid change (p.Asp154Asn) has been identified in ClinVar or the literature for KRAS or analogous RAS genes.
PS2
No de novo observation with confirmed maternity and paternity has been reported for this variant.
PS3
No variant-specific or systematic-range functional data from VCEP-approved assays (RAS activation, MEK/ERK activation) has been identified for p.Asp154Asn.
PS4
No case-control data or proband counts are available for this variant.
PM2
The VCEP PM2 rule requires the variant to be absent from gnomAD.
PM5
No different pathogenic or likely pathogenic missense variant at codon 154 was identified in ClinVar.
PM6
No assumed de novo observation (without confirmed parentage) has been reported for this variant.
PP1
No co-segregation data in affected family members is available for this variant.
PP3
The REVEL score is 0.19, below the VCEP PP3 threshold of ≥0.7.
Benign
BA1
The VCEP BA1 threshold is gnomAD filtering allele frequency ≥0.05%.
BS1
The VCEP BS1 threshold is gnomAD filtering allele frequency ≥0.025%.
BS2
No observation of this variant in healthy adult individuals has been reported.
BS4
No segregation data demonstrating lack of segregation in affected family members is available for this variant.
BP2
VCEP BP2 uses point-based scoring requiring observation of an alternative molecular cause of a RASopathy in the same gene alongside phenotypic data.
BP5
VCEP BP5 uses point-based scoring requiring an alternative molecular cause of a RASopathy in a different gene.
N/A · 8
PVS1 · PP2 · PP4 · PP5 · BS3 · BP1 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.24179e-06; MAF= 0.00012%, 2/1610578 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.23384e-05; MAF= 0.00223%, 1/44766 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00012%
· 2 / 1,610,578
0 hom
0 hom
East Asian 1 / 44,766 |
0.0022% |
European (non-Finnish) 1 / 1,177,160 |
8.5e-05% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.19. BayesDel score = -0.338537.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KRAS, a GTPase which functions as an upstream regulator of the MAPK pathway, is frequently mutated in various cancer types including lung, colorectal
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55736852, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links