About KRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KRAS c.40G>A, p.(Val14Ile)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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
confident-looking classification can still be wrong.
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: 5
Benign evidence criteria: 0
Pathogenic criteria applied · 5
PS3Moderate
PS3 · moderate
In the RASopathy VCEP approved functional studies, KRAS p.(Val14Ile) is listed among pathogenic validation controls in three approved assay classes cited to PMID:20949621: RAS activation, MEK activation, and ERK activation assays. This supports an abnormal KRAS signaling effect consistent with a gain-of-function mechanism.
PM1Moderate
PM1 · moderate
This missense variant affects KRAS residue 14, which lies within the P-loop (amino acids 10-17), a critical and well-established functional domain specified by the RASopathy VCEP for PM1 application.
PM6Supporting
PM6 · supporting
This variant was reported as a de novo germline KRAS mutation in Noonan syndrome in PMID:16474405. Because confirmation of both maternity and paternity was not identified in the inspected materials, the current evidence supports PM6 at a supporting level rather than PS2.
PP3Supporting
PP3 · supporting
Computational evidence supports a deleterious missense effect. REVEL is 0.803, which is above the VCEP PP3 threshold of 0.7, BayesDel is 0.289645, and SpliceAI predicts no significant splice impact with a max delta score of 0.01, supporting a missense rather than splicing mechanism.
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: Uncertain significance
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: PP5 supporting, PS3 moderate, PM1 moderate, PM6 supporting, PP3 supporting; no rule matched the adjudicated criteria.
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
2 / 1,612,846 alleles
gnomAD v4.1: 2 / 1,612,846 alleles. Recorded AF 1.24004e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/249502 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16070 alleles, homozygotes = 0).
No listed criterion applied
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: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant lies 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: 5 met · 5 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.40G>A (p.Val14Ile) variant has been reported in ClinVar as pathogenic, including expert panel review, and it was reported as a de novo germline KRAS mutation in Noonan syndrome.
This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 at 2/1612846 alleles (0.00012%), which is below the KRAS RASopathy VCEP benign frequency thresholds.
In the RASopathy VCEP approved functional studies, p.Val14Ile is listed as a pathogenic control in approved RAS activation, MEK activation, and ERK activation assay classes citing PMID:20949621, supporting abnormal KRAS signaling consistent with a gain-of-function effect.
Computational data support a damaging missense effect, with REVEL 0.803 above the PP3 threshold of 0.7, BayesDel 0.289645, and SpliceAI showing no significant splice impact (max delta score 0.01).
No criteria match.
Met · 5
PS3 ModerateIn the RASopathy VCEP approved functional studies, KRAS p.(Val14Ile) is listed among pathogenic validation controls in three approved assay classes cited to PMID:20949621: RAS activation, MEK activation, and ERK activation assays. This supports an abnormal KRAS signaling effect consistent with a gain-of-function mechanism. Details ▾Hide ▴
Rule
Two or more different approved assays.
Evidence considered
- V14I appears in approved RAS activation assay validation controls.
- V14I appears in approved MEK activation assay validation controls.
- V14I appears in approved ERK activation assay validation controls.
Still missing
- Direct extraction of the original assay figures and quantitative effect sizes from PMID:20949621 would further strengthen documentation.
Sources
PM1 ModerateThis missense variant affects KRAS residue 14, which lies within the P-loop (amino acids 10-17), a critical and well-established functional domain specified by the RASopathy VCEP for PM1 application. Details ▾Hide ▴
Rule
Applicable only to critical and well-established functional domains including the P-loop (AA 10-17).
Evidence considered
- KRAS codon 14 is within the P-loop AA10-17.
Sources
cspec ↗vcep_alignment_with_pm1_domains_pptx
PM6 SupportingThis variant was reported as a de novo germline KRAS mutation in Noonan syndrome in PMID:16474405. Because confirmation of both maternity and paternity was not identified in the inspected materials, the current evidence supports PM6 at a supporting level rather than PS2. Details ▾Hide ▴
Rule
0.5 Points.
Evidence considered
- Abstract snippet reports de novo germline KRAS mutations including V14I.
- ClinVar links this variant to published germline disease reports.
Still missing
- Need case-level confirmation of maternity and paternity and phenotype details to determine whether PS2 or stronger PM6 evidence can be applied.
Sources
PP3 SupportingComputational evidence supports a deleterious missense effect. REVEL is 0.803, which is above the VCEP PP3 threshold of 0.7, BayesDel is 0.289645, and SpliceAI predicts no significant splice impact with a max delta score of 0.01, supporting a missense rather than splicing mechanism. Details ▾Hide ▴
Rule
For missense variants: REVEL at least 0.7.
Evidence considered
- REVEL 0.803.
- BayesDel 0.289645.
- SpliceAI max delta score 0.01.
Sources
Not met · 5 · evaluated, threshold not reached
PS2 Available evidence supports a de novo report, but confirmation of both maternity and paternity was not identified in the inspected materials, so PS2 is not met on the current review. Details ▾Hide ▴
Rule
De novo with both maternity and paternity confirmed; point-based scoring with 1 point = Moderate, 2 points = Strong, 4 points = Very Strong.
Evidence considered
- Published abstract reports de novo germline KRAS mutations including V14I.
Still missing
- Need confirmed maternity and paternity plus case-level phenotype documentation to score PS2.
Sources
PM2 The VCEP requires absence from controls for PM2. This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 0.00012% (2/1612846 alleles), so the absence requirement is not met. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- gnomAD v2.1: 0/249502 alleles.
- gnomAD v4.1: 2/1612846 alleles
- total AF 0.00012%.
Sources
BA1 Population frequency is below the BA1 threshold. In gnomAD v4.1 the total allele frequency is 0.00012% (2/1612846), which is below the 0.05% threshold, and the variant is absent from gnomAD v2.1. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency at least 0.05%.
Evidence considered
- gnomAD v4.1 total AF 0.00012% (2/1612846).
- gnomAD v2.1 total AF 0/249502.
Sources
BS1 Population frequency is below the BS1 threshold. In gnomAD v4.1 the highest observed frequency is 0.00017% (2/1179292 non-Finnish European alleles), which is below the 0.025% threshold, and the variant is absent from gnomAD v2.1. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency at least 0.025%.
Evidence considered
- gnomAD v4.1 total AF 0.00012% (2/1612846)
- best subpopulation AF 0.00017%.
- gnomAD v2.1 total AF 0/249502.
Sources
BP4 Benign computational evidence is not met. REVEL is 0.803, which is above the BP4 threshold of 0.3, although SpliceAI predicts no significant splice impact with a max delta score of 0.01. Details ▾Hide ▴
Rule
For missense variants: REVEL at most 0.3.
Evidence considered
- REVEL 0.803.
- SpliceAI max delta score 0.01.
- BayesDel 0.289645.
Sources
Not assessed · 8 · no assessment recorded
PS1 No evidence was identified in the inspected materials showing the same amino acid change from a different nucleotide change, so PS1 was not assessed. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- PS1 requires the same amino acid change regardless of nucleotide change.
Still missing
- Need a previously established pathogenic KRAS p.Val14Ile variant from a different nucleotide change.
Sources
PS4 Affected-case observations are suggested by the literature and ClinVar, but the inspected materials did not provide a count of independent probands sufficient for the VCEP point-based PS4 framework, so PS4 was not assessed. Details ▾Hide ▴
Rule
At least 1 point = Supporting; at least 3 points = Moderate; at least 5 points = Strong.
Evidence considered
- ClinVar contains multiple pathogenic submissions including expert panel review.
- Published germline case reports are linked for this variant.
Still missing
- Need the number of unrelated affected probands and corresponding VCEP point assignment.
Sources
PM5 No same-codon pathogenic missense comparison was identified in the inspected materials, so PM5 was not assessed from the currently reviewed evidence. Details ▾Hide ▴
Rule
1 pathogenic residue change at the same codon = Moderate; at least 2 different pathogenic residue changes at the same codon observed in at least 5 probands = Strong.
Evidence considered
- VCEP allows PM5 for pathogenic changes at the same codon.
Still missing
- Need exact same-codon pathogenic variant evidence for KRAS codon 14 under the RASopathy VCEP framework.
Sources
PP1 No segregation data with informative meioses were identified, so PP1 was not assessed. Details ▾Hide ▴
Rule
At least 3 informative meioses = Supporting; at least 5 = Moderate; at least 7 = Strong.
Evidence considered
- No segregation evidence was extracted.
Still missing
- Need family-based segregation data with at least 3 informative meioses for PP1_Supporting.
Sources
BS2 No observations in unaffected individuals meeting the VCEP point-based BS2 framework were identified, so BS2 was not assessed. Details ▾Hide ▴
Rule
Point-based benign evidence from healthy individuals.
Evidence considered
- Population database entries alone do not establish unaffected status under the VCEP BS2 framework.
Still missing
- Need phenotyped unaffected heterozygous or homozygous individuals meeting the BS2 point thresholds.
Sources
BS4 No lack-of-segregation evidence was identified, so BS4 was not assessed. Details ▾Hide ▴
Rule
Requires only one informative meiosis.
Evidence considered
- No BS4-relevant family data were extracted.
Still missing
- Need informative family data showing non-segregation with disease.
Sources
BP2 No phase data or second pathogenic variant in the same gene were identified, so BP2 was not assessed. Details ▾Hide ▴
Rule
Point-based benign evidence using an alternative molecular cause in the same gene.
Evidence considered
- No BP2-relevant phase data were provided.
Still missing
- Need case-level phase information or a second molecular finding in KRAS.
Sources
BP5 No alternative molecular diagnosis explaining the phenotype was identified in the inspected evidence, so BP5 was not assessed. Details ▾Hide ▴
Rule
Point-based benign evidence for an alternative molecular explanation.
Evidence considered
- No alternate diagnosis data were provided.
Still missing
- Need case-level data showing a different molecular cause that fully explains the phenotype.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable in this VCEP framework, and this missense variant does not fall into the generic null-variant categories used for PVS1. Details ▾Hide ▴
Evidence considered
- Variant is missense and not a nonsense
- frameshift
- or canonical splice variant.
Sources
cspec ↗pvs1_variant_assessment
PM3 N/APM3 is not applicable in this VCEP framework. Details ▾Hide ▴
PM4 N/AThis variant does not change protein length, so PM4 is not applicable. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions or stop-loss variants.
Evidence considered
- Missense substitution p.(Val14Ile).
Sources
PP2 N/APP2 is not applicable for this VCEP framework. Details ▾Hide ▴
PP4 N/APP4 is not applicable in this VCEP framework because phenotype-based case evidence is handled through PS4. Details ▾Hide ▴
BS3 N/ABS3 is not applicable in this VCEP framework. Details ▾Hide ▴
BP1 N/AThis is a missense variant, whereas BP1 in this VCEP framework is reserved for truncating loss-of-function variants in genes without an established loss-of-function disease correlation. Details ▾Hide ▴
Rule
Use for truncating variants in genes without established loss-of-function correlation to disease.
Evidence considered
- Variant is missense p.(Val14Ile).
Sources
BP3 N/ABP3 is not applicable for this VCEP framework. Details ▾Hide ▴
BP6 N/ABP6 is not used in this VCEP framework. Details ▾Hide ▴
BP7 N/AThis is a missense variant, not a synonymous or non-coding change, so BP7 is not applicable. Details ▾Hide ▴
Rule
A synonymous or eligible non-coding variant with no predicted splice impact.
Evidence considered
- Missense change p.(Val14Ile).
Sources
Identifiers
- Gene
- KRAS
- Transcript
- NM_001369786.1
- Coding (HGVS c.)
- NM_001369786.1:c.40G>A
- Protein (HGVS p.)
- NP_001356715.1:p.(Val14Ile)
- GRCh38
- chr12:25245345 C>T
- GRCh37
- chr12:25398279 C>T
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
2 / 1,612,846 alleles
AF 1.24e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1
0 / 249,502 alleles
AF 0 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,612,846 alleles · 0 hom · FAF 2.8e-07
| European (non-Finnish)2 / 1,179,292 | 1.7e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 0 · 0 / 249,502 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.24004e-06; MAF= 0.00012%, 2/1612846 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69593e-06; MAF= 0.00017%, 2/1179292 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/249502 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16070 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingComputational evidence supports a deleterious missense effect. REVEL is 0.803, which is above the VCEP PP3 threshold of 0.7, BayesDel is 0.289645, and SpliceAI predicts no significant splice impact with a max delta score of 0.01, supporting a missense rather than splicing mechanism. Details ▾Hide ▴
Rule
For missense variants: REVEL at least 0.7.
Evidence considered
- REVEL 0.803.
- BayesDel 0.289645.
- SpliceAI max delta score 0.01.
Sources
BP4 Benign computational evidence is not met. REVEL is 0.803, which is above the BP4 threshold of 0.3, although SpliceAI predicts no significant splice impact with a max delta score of 0.01. Details ▾Hide ▴
Rule
For missense variants: REVEL at most 0.3.
Evidence considered
- REVEL 0.803.
- SpliceAI max delta score 0.01.
- BayesDel 0.289645.
Sources
BP7 N/AThis is a missense variant, not a synonymous or non-coding change, so BP7 is not applicable. Details ▾Hide ▴
Rule
A synonymous or eligible non-coding variant with no predicted splice impact.
Evidence considered
- Missense change p.(Val14Ile).
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.803. BayesDel score = 0.289645.
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
2 / 1,612,846 recorded alleles
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/12589/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-25398279-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-25245345-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001369786.1%3Ac.4…
- OncoKB ↗www.oncokb.org/gene/KRAS/V14I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=107973429
- 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
This variant is present in gnomAD v4.1 (AF= 1.24004e-06; MAF= 0.00012%, 2/1612846 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69593e-06; MAF= 0.00017%, 2/1179292 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/249502 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16070 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Pathogenic (19 clinical laboratories) and as 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 = 0.01). REVEL score = 0.803. BayesDel score = 0.289645.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55501342, n = 41 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.