The KRAS c.101C>T (p.Pro34Leu, p.P34L) variant has been reported in ClinVar as pathogenic and has been reviewed by the ClinGen RASopathy Variant Curation Expert Panel.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets.2 In published and VCEP-approved functional studies, this variant showed abnormal KRAS signaling behavior, including increased active GTP-bound KRAS and markedly reduced GAP-stimulated GTP hydrolysis with downstream pathway activation, consistent with a damaging gain-of-function effect.3 Computational evidence supports a deleterious missense effect, with REVEL 0.867 above the KRAS RASopathy PP3 threshold of 0.7, BayesDel 0.425277 supportive of pathogenicity, and SpliceAI showing no meaningful splice disruption (maximum delta score 0.02).4
KRAS
Final classification
Likely Pathogenic
KRAS c.101C>T · p.Pro34Leu
KRAS
The KRAS c.101C>T (p.Pro34Leu, p.P34L) variant has been reported in ClinVar as pathogenic and has been reviewed by 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: matched Rule14 (2 Pathogenic.Moderate + Pathogenic.Supporting >=2) with applied criteria: PS3 moderate, PM1 moderate, PM2 supporting, PM5 moderate, PP3 supporting, PP5 supporting; maps to Likely Pathogenic.
Classification rationale
PS3PM1PM2PM5PP3PP5
Likely Pathogenic
KRAS c.101C>T
PS3 + PM1 + PM2 + PM5 + PP3 + PP5
→
Likely Pathogenic
3
PMID:20949621 ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
4
revelbayesdelspliceai ↗cspec ↗
Gene diagram
· NM_001369786.1 · variants mapped to exon structure
KRAS
NM_001369786.1
Fetching transcript structure from UCSC…
Applied criteria · 6 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 · supports pathogenic
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 Pathogenic (7 clinical laboratories) 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 = 0.02). REVEL score = 0.867. BayesDel score = 0.425277.
Functional
Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
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; COSV55588721, n = 5 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
3papers 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:16474405
Found
Structured finding pending for this record — see source link.
Applied to
→PM5 supports · met
PMID PMID:17875937
Found
Structured finding pending for this record — see source link.
Applied to
→PM5 supports · met
PMID PMID:20949621
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links