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
KRAS
Final classification
VUS
KRAS c.15A>T · p.Lys5Asn
KRAS
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
Gene diagram
· NM_001369786.1 · variants mapped to exon structure
KRAS
NM_001369786.1
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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.
PMID PMID:20949621
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links