Variant classification summary

NM_033360.3:c.460G>A

KRAS · NP_203524.1:p.(Asp154Asn) · NM_033360.3

GRCh37: chr12:25368485 C>T · GRCh38: chr12:25215551 C>T

Gene: KRAS Transcript: NM_033360.3

Final call

VUS

PM1 moderate BP4 supporting benign

Variant details

Gene

KRAS

Transcript

NM_033360.3

Protein

NP_203524.1:p.(Asp154Asn)

gnomAD AF

1.2417902144447522e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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).

3

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).

4

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.'

5

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.

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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	PVS1 is not applicable per ClinGen RASopathy VCEP v2.3.0; this is a missense variant (c.460G>A, p.Asp154Asn), not a null variant.	cspec
PS1	Not met	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.	clinvar
PS2	Not met	No de novo observation with confirmed maternity and paternity has been reported for this variant.
PS3	Not met	No variant-specific or systematic-range functional data from VCEP-approved assays (RAS activation, MEK/ERK activation) has been identified for p.Asp154Asn. OncoKB lists this variant as 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence.	oncokb vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not met	No case-control data or proband counts are available for this variant. The variant is absent from ClinVar with no submitter-reported proband data.	clinvar
PS5	N/A	PS5 is not defined in the ClinGen RASopathy VCEP v2.3.0 criteria framework; this criterion is not applicable.	cspec
PM1	Met	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.	cspec
PM2	Not met	The VCEP PM2 rule requires the variant to be absent from gnomAD. This variant is present in gnomAD v4.1 at an extremely low frequency (2/1,610,578 alleles, AF=1.24e-6), and is absent from gnomAD v2.1. Because it is technically present in gnomAD v4.1, the strict 'absent' requirement is not satisfied.	gnomad_v2 gnomad_v4
PM5	Not met	No different pathogenic or likely pathogenic missense variant at codon 154 was identified in ClinVar. No PM5 comparator candidates were found.	pm5_candidates clinvar
PM6	Not met	No assumed de novo observation (without confirmed parentage) has been reported for this variant.
PP1	Not met	No co-segregation data in affected family members is available for this variant.
PP2	N/A	PP2 is not applicable per ClinGen RASopathy VCEP v2.3.0 because the KRAS missense z-score is <3.09 in gnomAD.	cspec
PP3	Not met	The REVEL score is 0.19, below the VCEP PP3 threshold of ≥0.7. SpliceAI predicts no significant splice impact (max delta score 0.10). Multiple in silico predictors support a benign impact.	revel bayesdel spliceai
PP4	N/A	PP4 is not applicable per ClinGen RASopathy VCEP v2.3.0.	cspec
PP5	N/A	PP5 is not applicable per ClinGen RASopathy VCEP v2.3.0; this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	The VCEP BA1 threshold is gnomAD filtering allele frequency ≥0.05%. This variant has an allele frequency of 0.00012% (1.24e-6) in gnomAD v4.1, far below the stand-alone benign threshold.	gnomad_v4
BS1	Not met	The VCEP BS1 threshold is gnomAD filtering allele frequency ≥0.025%. This variant has an allele frequency of 0.00012% in gnomAD v4.1, far below the strong benign threshold.	gnomad_v4
BS2	Not met	No observation of this variant in healthy adult individuals has been reported. The VCEP point-based scoring system requires phenotypic data not available for this variant.
BS3	N/A	BS3 is not applicable per ClinGen RASopathy VCEP v2.3.0.	cspec
BS4	Not met	No segregation data demonstrating lack of segregation in affected family members is available for this variant.
BP1	N/A	BP1 per the RASopathy VCEP applies only to truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, gene deletions) in genes without established LOF correlation. This is a missense variant and BP1 does not apply.	cspec
BP2	Not met	VCEP BP2 uses point-based scoring requiring observation of an alternative molecular cause of a RASopathy in the same gene alongside phenotypic data. No such data is available for this variant.
BP4	Met	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 bayesdel spliceai
BP5	Not met	VCEP BP5 uses point-based scoring requiring an alternative molecular cause of a RASopathy in a different gene. No such data is available for this variant.
BP6	N/A	BP6 is not applicable per ClinGen RASopathy VCEP v2.3.0.	cspec
BP7	N/A	BP7 applies only to synonymous (silent) variants. NM_033360.3:c.460G>A is a missense variant (p.Asp154Asn) and BP7 does not apply.	cspec

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