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.1 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.2 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.3 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).4
Final classification
VUS
PP5PS3PM1PM6PP3
KRAS
c.40G>A
p.Val14Ile
This variant
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.
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.
Classification rationale
PP5PS3PM1PM6PP3
VUS
KRAS c.40G>A
PP5 + PS3 + PM1 + PM6 + PP3
→
VUS
3
vcep_svi_rasopathy_vcep_v2_approved_functional_studiesPMID:20949621 ↗
4
cspec ↗revelbayesdelspliceai ↗
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 · 5 applied · 13 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 · 5
Strength
Supporting
Moderate
Strong
Very strong
PS3
moderate
review
Pathogenic
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.
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.
PM1
moderate
Pathogenic
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.
KRAS codon 14 is within the P-loop AA10-17.
PM6
supporting
review
Pathogenic
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.
Abstract snippet reports de novo germline KRAS mutations including V14I.ClinVar links this variant to published germline disease reports.
PP3
supporting
Pathogenic
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.
REVEL 0.803.BayesDel 0.289645.SpliceAI max delta score 0.01.
Assessed · not applied
· 5 not met · 8 not assessed
Pathogenic
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.
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.
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.
PM2
The VCEP requires absence from controls for PM2.
PM5
No same-codon pathogenic missense comparison was identified in the inspected materials, so PM5 was not assessed from the currently reviewed evidence.
PP1
No segregation data with informative meioses were identified, so PP1 was not assessed.
Benign
BA1
Population frequency is below the BA1 threshold.
BS1
Population frequency is below the BS1 threshold.
BS2
No observations in unaffected individuals meeting the VCEP point-based BS2 framework were identified, so BS2 was not assessed.
BS4
No lack-of-segregation evidence was identified, so BS4 was not assessed.
BP2
No phase data or second pathogenic variant in the same gene were identified, so BP2 was not assessed.
BP4
Benign computational evidence is not met.
BP5
No alternative molecular diagnosis explaining the phenotype was identified in the inspected evidence, so BP5 was not assessed.
N/A · 10
PVS1 · PM3 · PM4 · PP2 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
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).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00012%
· 2 / 1,612,846
0 hom · FAF 2.8e-05%
0 hom · FAF 2.8e-05%
European (non-Finnish) 2 / 1,179,292 |
0.00017% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / 249,502
0 hom
0 hom
Not observed in any ancestry group.
+ 8 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
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
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; COSV55501342, n = 41 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
2papers 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
Structured finding pending for this record — see source link.
Applied to
→PM6
supporting
Germline KRAS mutations cause aberrant biochemical and physical properties leadi
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
moderate
Sources & reference links