The KRAS c.15A>T (p.(Lys5Asn), p.(K5N)) variant has been observed in somatic cancers in COSMIC (COSV56100680, 2 occurrences) and has been reported in ClinVar, including a Pathogenic expert-panel classification from the ClinGen RASopathy Variant Curation Expert Panel.1 This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population databases.2 In approved functional studies used by the RASopathy VCEP, p.(Lys5Asn) showed abnormal results in both MEK activation and ERK activation assays, and published KRAS functional work described aberrant biochemical properties of germline KRAS variants consistent with a gain-of-function effect.3 Computational evidence supports a deleterious missense effect because REVEL is 0.764, which is above the KRAS RASopathy PP3 threshold of 0.7, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.19; BayesDel is 0.0213364.4
Final classification
VUS
PS3PM2PP3PP5
KRAS
c.15A>T
p.Lys5Asn
This variant
The KRAS c.15A>T (p.(Lys5Asn), p.(K5N)) variant has been observed in somatic cancers in COSMIC (COSV56100680, 2 occurrences) and has been reported in ClinVar, including a Pathogenic expert-panel classification from the ClinGen RASopathy Variant Curation Expert Panel.
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: PS3 moderate, PM2 supporting, PP3 supporting, PP5 supporting; no rule matched the adjudicated criteria.
Classification rationale
PS3PM2PP3PP5
VUS
KRAS c.15A>T
PS3 + PM2 + PP3 + PP5
→
VUS
3
vcep_svi_rasopathy_vcep_v2_approved_functional_studiesPMID:20949621 ↗
4
cspec ↗revelspliceai ↗bayesdel
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.
Gene diagram
· NM_001369786.1 · variants mapped to exon structure
KRAS
NM_001369786.1
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 14 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
PS3
moderate
review
Pathogenic
Approved KRAS functional studies in the RASopathy VCEP materials list p.(Lys5Asn) among pathogenic variants showing abnormal results in two different approved assays, MEK activation and ERK activation, and the cited KRAS functional literature describes aberrant biochemical properties of germline KRAS variants consistent with a gain-of-function effect. This supports PS3 at the Moderate level under the KRAS RASopathy specification.
RASopathy VCEP approved functional study workbookMEK activation assay includes K5N among pathogenic KRAS variantsERK activation assay includes K5N among pathogenic KRAS variants
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. Under the KRAS RASopathy specification, absence from controls supports PM2 at the Supporting level.
gnomAD v2.1 absentgnomAD v4.1 absentKRAS RASopathy PM2 requires absence from controls
PP3
supporting
Pathogenic
For this missense variant, REVEL is 0.764, which is above the KRAS RASopathy PP3 threshold of at least 0.7. SpliceAI predicts no significant splice effect with a maximum delta score of 0.19, supporting interpretation as a missense rather than splicing mechanism, and BayesDel is also available at 0.0213364. These data support PP3 at the Supporting level.
REVEL 0.764SpliceAI max delta 0.19BayesDel 0.0213364
Assessed · not applied
· 4 not met · 10 not assessed
Pathogenic
PS1
No retrieved evidence established a different nucleotide change producing the same KRAS p.(Lys5Asn) amino acid substitution as a previously established pathogenic variant, so PS1 was not applied.
PS2
No confirmed de novo occurrence with parental relationship and testing details was identified in the retrieved evidence, so PS2 was not applied.
PS4
Although this variant is present in ClinVar and has been observed in somatic cancers, the retrieved evidence did not provide the point-based proband counts or enrichment data required by the KRAS RASopathy specification for PS4.
PM1
The KRAS RASopathy specification limits PM1 to the P-loop (amino acids 10-17), Switch I (25-40), Switch II (57-64), and SAK (145-156) domains.
PM5
The retrieved evidence did not document a different established pathogenic missense change at KRAS codon 5 with the case-count detail needed to assign PM5 under the KRAS RASopathy specification, so PM5 was not applied.
PM6
No presumed or confirmed de novo evidence with sufficient case-level detail was identified in the retrieved materials, so PM6 was not applied.
PP1
No segregation data were identified showing that this variant tracks with disease across informative meioses, so PP1 was not applied.
Benign
BA1
This variant is absent from gnomAD v2.1 and v4.1 and therefore does not meet the KRAS RASopathy BA1 threshold of at least 0.05% filtering allele frequency.
BS1
This variant is absent from gnomAD v2.1 and v4.1 and therefore does not meet the KRAS RASopathy BS1 threshold of at least 0.025% filtering allele frequency.
BS2
No evidence was identified showing this variant in unaffected individuals at the point level required by the KRAS RASopathy specification, so BS2 was not applied.
BS4
No non-segregation data were identified showing this variant in unaffected relatives or lack of tracking with disease, so BS4 was not applied.
BP2
No phase information or alternative molecular diagnosis evidence was identified to support BP2, so this criterion was not applied.
BP4
For missense variants, the KRAS RASopathy BP4 threshold requires REVEL of 0.3 or lower.
BP5
No alternative molecular explanation or phenotype-based point evidence was identified to support BP5, so this criterion was not applied.
N/A · 10
PVS1 · PM3 · PM4 · PP2 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.19). REVEL score = 0.764. BayesDel score = 0.0213364.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56100680, n = 2 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Germline KRAS mutations cause aberrant biochemical and physical properties leadi
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
moderate
Sources & reference links