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
Final classification
Likely Pathogenic
PS3PM1PM2PM5PP3PP5
KRAS
c.101C>T
p.Pro34Leu
This variant
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 ↗
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 · 6 applied · 12 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 · 6
Strength
Supporting
Moderate
Strong
Very strong
PS3
moderate
Pathogenic
In approved KRAS functional assays, this variant showed abnormal signaling behavior consistent with a damaging gain-of-function effect. Published experiments reported increased active GTP-bound KRAS, marked reduction of GAP-stimulated GTP hydrolysis for P34L comparable to oncogenic G12V, and downstream pathway activation; the RASopathy VCEP functional-study file lists this variant as a pathogenic control in RAS activation, MEK activation, and ERK activation assays. This supports PS3 at Moderate strength because at least two different approved assays are available.
PMID:20949621 evaluated p.P34L among 10 germline KRAS mutants.P34L showed increased GTP-bound KRAS and severe reduction of GAP-stimulated GTPase activity.VCEP-approved functional-study spreadsheet lists P34L as a pathogenic control in RAS activation
PM1
moderate
Pathogenic
This missense change affects codon 34, which lies within the KRAS Switch I domain. The KRAS RASopathy specification defines Switch I as amino acids 25-40, a critical and well-established functional domain for PM1, so PM1 is met at Moderate strength.
Protein consequence is p.Pro34Leu/p.P34L.KRAS Switch I domain is specified as amino acids 25-40.
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, meeting the KRAS RASopathy requirement that the variant be absent from controls.
Absent from gnomAD v2.1.Absent from gnomAD v4.1.
PM5
moderate
Pathogenic
A different pathogenic missense change has been reported at this same codon. Specifically, KRAS p.Pro34Arg has been reported in an individual with cardio-facio-cutaneous syndrome and is discussed in subsequent functional literature, supporting PM5 at Moderate strength for this novel residue change at codon 34.
PMID:16474405 reports KRAS p.Pro34Arg in an affected individual.PMID:17875937 discusses KRAS codon 34 disease-associated substitutions including P34R.
PP3
supporting
Pathogenic
Computational evidence supports a deleterious missense effect. REVEL is 0.867, which is above the KRAS RASopathy PP3 threshold of 0.7; BayesDel is 0.425277, also supporting a damaging effect; and SpliceAI predicts no meaningful splice disruption with a maximum delta score of 0.02, indicating the concern is the missense change rather than altered splicing. This meets PP3 at Supporting strength.
REVEL 0.867.BayesDel 0.425277.SpliceAI max delta 0.02.
Assessed · not applied
· 4 not met · 8 not assessed
Pathogenic
PS1
No reviewed source identified a different nucleotide change that produces this same amino acid substitution and is independently established as pathogenic, so PS1 is not met.
PS2
No confirmed de novo observation with verified maternity and paternity was identified for this variant in the reviewed sources, so PS2 cannot be assigned from the available evidence.
PS4
Although this variant has been reported in affected individuals and is classified as pathogenic in ClinVar, the reviewed sources did not provide a verified proband count or point total required for PS4 under the KRAS RASopathy specification.
PM6
No reviewed source provided sufficient evidence that this variant occurred de novo without confirmed maternity and paternity, so PM6 cannot be assigned from the available data.
PP1
No segregation data were identified for this variant, so PP1 is not met from the available evidence.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BA1 threshold of 0.05%, so BA1 is not met.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BS1 threshold of 0.025%, so BS1 is not met.
BS2
No observations in unaffected individuals were identified, so BS2 cannot be assessed from the available evidence.
BS4
No non-segregation data were identified for this variant, so BS4 cannot be assessed from the available evidence.
BP2
No evidence was identified that this variant was observed with another pathogenic variant in a context relevant to the KRAS RASopathy BP2 point framework.
BP4
Computational evidence does not support a benign effect.
BP5
No alternate molecular diagnosis or clearly inconsistent phenotype was identified, so BP5 cannot be assessed from the available evidence.
N/A · 10
PVS1 · PM3 · PM4 · PP2 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7
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.
Germline KRAS mutations cause Noonan syndrome.
Found
reports KRAS p.Pro34Arg in an affected individual.
Applied to
→PM5
moderate
Biochemical and functional characterization of germ line KRAS mutations.
Found
discusses KRAS codon 34 disease-associated substitutions including P34R.
Applied to
→PM5
moderate
Germline KRAS mutations cause aberrant biochemical and physical properties leadi
Found
evaluated p.P34L among 10 germline KRAS mutants.
Applied to
→PS3
moderate
Sources & reference links