About KRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KRAS c.101C>T, p.(Pro34Leu)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
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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: 6
Benign evidence criteria: 0
Pathogenic criteria applied · 6
PS3Moderate
PS3 · moderate
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.
PM1Moderate
PM1 · moderate
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.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, meeting the KRAS RASopathy requirement that the variant be absent from controls.
PM5Moderate
PM5 · moderate
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.
PP3Supporting
PP3 · supporting
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.
PP5Supporting
PP5 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
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.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
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 assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen KRAS VCEP v2.3.0, with the data and sources behind each one.
28 criteria with recorded statuses: 6 met · 4 not met · 8 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets.
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.
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).
No criteria match.
Met · 6
PS3 ModerateIn 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. Details ▾Hide ▴
Rule
Two or more different approved assays.
Evidence considered
- 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
- MEK activation
- and ERK activation assays.
Sources
PM1 ModerateThis 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. Details ▾Hide ▴
Rule
Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]). Not applicable to specific amino acid residues (see PM5).
Evidence considered
- Protein consequence is p.Pro34Leu/p.P34L.
- KRAS Switch I domain is specified as amino acids 25-40.
Sources
cspec ↗vcep_alignment_with_pm1_domains_pptx
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, meeting the KRAS RASopathy requirement that the variant be absent from controls. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
PM5 ModerateA 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. Details ▾Hide ▴
Rule
1 [likely] pathogenic residue change at the same codon.
Evidence considered
- PMID:16474405 reports KRAS p.Pro34Arg in an affected individual.
- PMID:17875937 discusses KRAS codon 34 disease-associated substitutions including P34R.
Sources
PP3 SupportingComputational 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. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.867.
- BayesDel 0.425277.
- SpliceAI max delta 0.02.
Sources
Not met · 4 · evaluated, threshold not reached
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. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in HRAS, KRAS, MRAS, NRAS, RIT1, and RRAS2.
Evidence considered
- Reviewed sources document this exact amino acid change but do not provide a different nucleotide change causing the same amino acid substitution.
Still missing
- A directly documented alternate nucleotide change encoding p.Pro34Leu would be needed to apply PS1.
Sources
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. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.05%.
Evidence considered
- Observed population frequency is 0 in reviewed gnomAD datasets.
Sources
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. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.025%.
Evidence considered
- Observed population frequency is 0 in reviewed gnomAD datasets.
Sources
BP4 Computational evidence does not support a benign effect. REVEL is 0.867, which is above the benign BP4 threshold of 0.3, and BayesDel is positive at 0.425277; SpliceAI predicts little splice impact with a maximum delta score of 0.02, but the missense-prediction evidence overall does not support BP4. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3.
Evidence considered
- REVEL 0.867 exceeds the BP4 benign cutoff.
- BayesDel 0.425277 is not supportive of benignity.
- SpliceAI max delta 0.02 indicates little splice impact but does not overcome deleterious missense predictions.
Sources
Not assessed · 8 · no assessment recorded
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. Details ▾Hide ▴
Rule
Follow SVI recommendations for point-based scoring in conjunction with PM6 and phenotypic specifications.
Evidence considered
- No confirmed de novo evidence for p.Pro34Leu was available in the reviewed case materials.
Still missing
- Case-level documentation of a confirmed de novo occurrence with parental relationships established.
- Point total under the RASopathy de novo scoring framework.
Sources
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. Details ▾Hide ▴
Rule
Strong ≥5 points; Moderate ≥3 points; Supporting ≥1 point.
Evidence considered
- ClinVar lists the variant as pathogenic with expert-panel review.
- Case-observation literature is cited in the reviewed materials
- but PS4 point scoring could not be verified from the available data.
Still missing
- Verified number of independent affected probands with this variant.
- RASopathy phenotype details for each proband.
- PS4 point total under the VCEP framework.
Sources
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. Details ▾Hide ▴
Rule
Strong 2 Points; Moderate 1 Point; Supporting 0.5 Points.
Evidence considered
- No usable PM6-grade de novo evidence for p.Pro34Leu was available in the reviewed materials.
Still missing
- Case-level statement that the variant was absent in parents but without formal parentage confirmation.
- PM6 point total under the RASopathy de novo framework.
Sources
PP1 No segregation data were identified for this variant, so PP1 is not met from the available evidence. Details ▾Hide ▴
Rule
Supporting ≥3 informative meioses; Moderate ≥5 informative meioses; Strong ≥7 informative meioses.
Evidence considered
- No family segregation evidence for p.Pro34Leu was available in the reviewed materials.
Still missing
- Informative meioses showing segregation with disease.
Sources
BS2 No observations in unaffected individuals were identified, so BS2 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
Strong -4 Points; Supporting -1 Point.
Evidence considered
- No healthy-carrier data were available in the reviewed materials.
Still missing
- Documented unaffected carriers meeting the RASopathy BS2 point framework.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
Requires only one informative meiosis.
Evidence considered
- No informative non-segregation evidence for p.Pro34Leu was available in the reviewed materials.
Still missing
- Family data showing lack of segregation with disease.
Sources
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. Details ▾Hide ▴
Rule
Strong ≥(-4) points; Moderate ≥(-2) points; Supporting ≥(-1) point.
Evidence considered
- No BP2-relevant molecular context was available in the reviewed materials.
Still missing
- Phase and phenotype data showing an alternate molecular explanation in the same gene.
Sources
BP5 No alternate molecular diagnosis or clearly inconsistent phenotype was identified, so BP5 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
Strong ≥(-4) points; Moderate ≥(-2) points; Supporting ≥(-1) point.
Evidence considered
- No BP5-relevant alternate diagnosis data were available in the reviewed materials.
Still missing
- A documented alternate molecular cause explaining the phenotype or a clearly non-RASopathy presentation fully explained by another variant.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the KRAS RASopathy specification marks PVS1 as not applicable for this gene-disease framework. Details ▾Hide ▴
Evidence considered
- Missense variant p.(Pro34Leu)/p.(P34L).
- KRAS RASopathy specification lists PVS1 as not applicable.
Sources
PM3 N/APM3 is not applicable in the KRAS RASopathy specification. Details ▾Hide ▴
PM4 N/AThis is not an in-frame insertion/deletion or stop-loss variant, so PM4 does not apply. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Evidence considered
- Variant type is missense.
Sources
PP2 N/APP2 is not applicable in this KRAS RASopathy framework. Details ▾Hide ▴
PP4 N/APP4 is not applicable in the KRAS RASopathy specification. Details ▾Hide ▴
BS3 N/ABS3 is not applicable in this KRAS RASopathy framework. Details ▾Hide ▴
BP1 N/ABP1 in this framework is reserved for truncating loss-of-function variants in genes without established loss-of-function disease correlation, and this variant is missense. Details ▾Hide ▴
Rule
Use for truncating variants in genes without established LOF correlation to disease.
Evidence considered
- Variant type is missense.
Sources
BP3 N/ABP3 is not applicable in the KRAS RASopathy specification. Details ▾Hide ▴
BP6 N/ABP6 is not used in this VCEP framework. Details ▾Hide ▴
BP7 N/AThis is not a synonymous or noncoding variant, so BP7 does not apply. Details ▾Hide ▴
Rule
A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Evidence considered
- Variant type is missense.
Sources
Identifiers
- Gene
- KRAS
- Transcript
- NM_001369786.1
- Coding (HGVS c.)
- NM_001369786.1:c.101C>T
- Protein (HGVS p.)
- NP_001356715.1:p.(Pro34Leu)
- GRCh38
- chr12:25245284 G>A
- GRCh37
- chr12:25398218 G>A
Gene diagram
Every interpreted variant in KRAS, mapped onto the exon structure of NM_001369786.1. Select a row to find it on the plot.
KRASNM_001369786.1
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in KRAS
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingComputational 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. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.867.
- BayesDel 0.425277.
- SpliceAI max delta 0.02.
Sources
BP4 Computational evidence does not support a benign effect. REVEL is 0.867, which is above the benign BP4 threshold of 0.3, and BayesDel is positive at 0.425277; SpliceAI predicts little splice impact with a maximum delta score of 0.02, but the missense-prediction evidence overall does not support BP4. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3.
Evidence considered
- REVEL 0.867 exceeds the BP4 benign cutoff.
- BayesDel 0.425277 is not supportive of benignity.
- SpliceAI max delta 0.02 indicates little splice impact but does not overcome deleterious missense predictions.
Sources
BP7 N/AThis is not a synonymous or noncoding variant, so BP7 does not apply. Details ▾Hide ▴
Rule
A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Evidence considered
- Variant type is missense.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.867. BayesDel score = 0.425277.
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
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
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243114
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/40454/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-25398218-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-25245284-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001369786.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/KRAS/P34L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=107976085
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
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
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55588721, n = 5 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.