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
KRAS
Final classification
VUS
KRAS c.40G>A · p.Val14Ile
KRAS
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 ↗
Gene diagram
· NM_001369786.1 · variants mapped to exon structure
KRAS
NM_001369786.1
Fetching transcript structure from UCSC…
Applied criteria · 5 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
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.
PMID PMID:16474405
Found
Structured finding pending for this record — see source link.
Applied to
→PM6 supports · met
PMID PMID:20949621
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links