0%
KRASc.460G>AUncertain significance
Print report
Variant interpretation report

KRAS c.460G>A, p.(Asp154Asn)

NM_033360.3:c.460G>A NP_203524.1:p.(Asp154Asn) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About KRAS

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen KRAS VCEP v2.3.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM1Moderate
PM1 · moderate

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
2 / 1,610,578 alleles

gnomAD v4.1: 2 / 1,610,578 alleles. Recorded AF 1.24179e-06. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.100 maximum delta

Recorded SpliceAI maximum delta score: 0.100. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV55736852, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen KRAS VCEP v2.3.0, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 15 not met · 0 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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).

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).

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.'

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.

Met · 2

PM1 ModerateThe 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. Details ▾Hide ▴
Evidence considered
  • VCEP-defined SAK domain spans AA 145-156
  • variant p.Asp154Asn is at position 154 within this domain
Sources
cspec ↗
BP4 SupportingThe 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. Details ▾Hide ▴
Evidence considered
  • REVEL=0.19 (≤0.3 VCEP BP4 threshold)
  • BayesDel=-0.339
  • SpliceAI max delta=0.10
Sources
revelbayesdelspliceai ↗

Not met · 15 · evaluated, threshold not reached

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. Details ▾Hide ▴
Evidence considered
  • This variant is absent from ClinVar
  • no p.Asp154Asn established as pathogenic in any RAS gene
Sources
clinvar ↗
PS2 No de novo observation with confirmed maternity and paternity has been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo data available for this variant
Still missing
  • No proband phenotype or family history data available
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional studies identified in VCEP-approved assay compendium
Still missing
  • No functional studies have tested this specific variant in any VCEP-approved assay
Sources
oncokb ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4 No case-control data or proband counts are available for this variant. The variant is absent from ClinVar with no submitter-reported proband data. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no prevalence data in affected individuals
Still missing
  • No proband or case-control data available
Sources
clinvar ↗
PM2 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. Details ▾Hide ▴
Evidence considered
  • Present in gnomAD v4.1 at 2/1
  • 610
  • 578 alleles (AF=1.24e-6)
  • absent from gnomAD v2.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM5 No different pathogenic or likely pathogenic missense variant at codon 154 was identified in ClinVar. No PM5 comparator candidates were found. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search returned no same-residue comparator variants at codon 154
Sources
pm5_candidatesclinvar ↗
PM6 No assumed de novo observation (without confirmed parentage) has been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo data available
Still missing
  • No proband data available
PP1 No co-segregation data in affected family members is available for this variant. Details ▾Hide ▴
Evidence considered
  • No segregation data available
Still missing
  • No family segregation data available
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL=0.19 (<0.7 threshold)
  • BayesDel=-0.339
  • SpliceAI max delta=0.10
Sources
revelbayesdelspliceai ↗
BA1 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=0.00012% (2/1
  • 610
  • 578)
  • well below the 0.05% BA1 threshold
Sources
gnomad_v4 ↗
BS1 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=0.00012%
  • well below the 0.025% BS1 threshold
Sources
gnomad_v4 ↗
BS2 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. Details ▾Hide ▴
Evidence considered
  • No healthy adult carrier data available
Still missing
  • No phenotypic data for gnomAD carriers
BS4 No segregation data demonstrating lack of segregation in affected family members is available for this variant. Details ▾Hide ▴
Evidence considered
  • No family segregation data available
Still missing
  • No family studies available
BP2 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. Details ▾Hide ▴
Evidence considered
  • No alternative molecular cause or co-occurrence data available
Still missing
  • No proband-level molecular data available
BP5 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. Details ▾Hide ▴
Evidence considered
  • No alternative molecular cause identified in a different gene
Still missing
  • No proband-level molecular data available
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPPVS1 is not applicable per ClinGen RASopathy VCEP v2.3.0; this is a missense variant (c.460G>A, p.Asp154Asn), not a null variant. Details ▾Hide ▴
Evidence considered
  • VCEP criteria list PVS1 applicability as 'Not applicable'
Sources
cspec ↗
PP2 VCEPPP2 is not applicable per ClinGen RASopathy VCEP v2.3.0 because the KRAS missense z-score is <3.09 in gnomAD. Details ▾Hide ▴
Evidence considered
  • VCEP deems PP2 not applicable for KRAS (missense z-score < 3.09)
Sources
cspec ↗
PP4 VCEPPP4 is not applicable per ClinGen RASopathy VCEP v2.3.0. Details ▾Hide ▴
Evidence considered
  • VCEP deems PP4 'Not Applicable'
Sources
cspec ↗
PP5 VCEPPP5 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. Details ▾Hide ▴
Evidence considered
  • VCEP deems PP5 'Not Applicable for this VCEP'
Sources
cspec ↗
BS3 VCEPBS3 is not applicable per ClinGen RASopathy VCEP v2.3.0. Details ▾Hide ▴
Evidence considered
  • VCEP deems BS3 'Not applicable'
Sources
cspec ↗
BP1 N/ABP1 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. Details ▾Hide ▴
Evidence considered
  • VCEP BP1 rule is restricted to truncating variants
  • c.460G>A is a missense variant
Sources
cspec ↗
BP6 VCEPBP6 is not applicable per ClinGen RASopathy VCEP v2.3.0. Details ▾Hide ▴
Evidence considered
  • VCEP deems BP6 'Not Applicable'
Sources
cspec ↗
BP7 N/ABP7 applies only to synonymous (silent) variants. NM_033360.3:c.460G>A is a missense variant (p.Asp154Asn) and BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • BP7 is restricted to synonymous variants
  • c.460G>A is missense
Sources
cspec ↗
PS5 N/APS5 is not defined in the ClinGen RASopathy VCEP v2.3.0 criteria framework; this criterion is not applicable. Details ▾Hide ▴
Evidence considered
  • PS5 is not listed in the VCEP criteria
Sources
cspec ↗

Identifiers

Gene
KRAS
Transcript
NM_033360.3
Coding (HGVS c.)
NM_033360.3:c.460G>A
Protein (HGVS p.)
NP_203524.1:p.(Asp154Asn)
GRCh38
chr12:25215551 C>T
GRCh37
chr12:25368485 C>T
COSMIC
COSV55736852

Gene diagram

Every interpreted variant in KRAS, mapped onto the exon structure of NM_033360.3. Select a row to find it on the plot.

KRASNM_033360.3
Fetching transcript structure from UCSC…
gnomAD v4.1 2 / 1,610,578 alleles AF 1.24e-06 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.2e-06 · 2 / 1,610,578 alleles · 0 hom
East Asian1 / 44,766 2.2e-05
European (non-Finnish)1 / 1,177,160 8.5e-07
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +9 bp
0.100
SpliceAI acceptor gainat +7 bp
0.000
SpliceAI donor lossat -114 bp
0.090
SpliceAI donor gainat +64 bp
0.000
Pangolin splice lossmagnitude shown
-0.160
Pangolin splice gain
0.000

Other predictors

REVEL
0.190
BayesDel
-0.339

How the predictions were used

BP4 SupportingThe 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. Details ▾Hide ▴
Evidence considered
  • REVEL=0.19 (≤0.3 VCEP BP4 threshold)
  • BayesDel=-0.339
  • SpliceAI max delta=0.10
Sources
revelbayesdelspliceai ↗
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL=0.19 (<0.7 threshold)
  • BayesDel=-0.339
  • SpliceAI max delta=0.10
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies only to synonymous (silent) variants. NM_033360.3:c.460G>A is a missense variant (p.Asp154Asn) and BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • BP7 is restricted to synonymous variants
  • c.460G>A is missense
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.19. BayesDel score = -0.338537.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 2 / 1,610,578 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.100 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

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

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

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55736852, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.