The KRAS c.194G>T (p.Ser65Ile) variant has been reported in ClinVar, including a Likely pathogenic expert-panel classification and additional pathogenic and uncertain-significance submissions.1 This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting PM2 at supporting strength under the KRAS RASopathy specification.2 Available KRAS VCEP functional-study materials list approved assay types for this gene, but no variant-specific approved functional result for p.Ser65Ile was identified in the retrieved evidence, so PS3 was not applied.3 Computational data do not meet the KRAS RASopathy missense thresholds for either PP3 or BP4: REVEL is 0.60, which is below the PP3 threshold of at least 0.7 and above the BP4 threshold of 0.3 or lower, BayesDel is 0.0836572, and SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01.4
Final classification
VUS
PM2PP5
KRAS
c.194G>T
p.Ser65Ile
This variant
The KRAS c.194G>T (p.Ser65Ile) variant has been reported in ClinVar, including a Likely pathogenic expert-panel classification and additional pathogenic and uncertain-significance submissions.
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: PM2 supporting, PP5 supporting; no rule matched the adjudicated criteria.
Classification rationale
PM2PP5
VUS
KRAS c.194G>T
PM2 + PP5
→
VUS
3
vcep_svi_rasopathy_vcep_v2_approved_functional_studiesoncokb ↗
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 · 2 applied · 16 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which meets the KRAS RASopathy VCEP PM2 requirement that the variant be absent from controls.
gnomAD v2.1 absentgnomAD v4.1 absentVCEP PM2 threshold is absence from controls
Assessed · not applied
· 5 not met · 11 not assessed
Pathogenic
PS1
No prior pathogenic variant causing the same amino acid change by a different nucleotide change was identified in the retrieved evidence, so PS1 was not applied.
PS2
No confirmed de novo occurrence with sufficient parental testing and phenotype detail was identified, so PS2 was not applied.
PS3
Available KRAS functional-study materials list approved assay types for this gene, but no variant-specific approved functional result for p.(Ser65Ile) was identified in the retrieved evidence, so PS3 was not applied.
PS4
The variant has been reported in ClinVar, but the retrieved evidence did not provide enough case-level data to score affected-individual enrichment under the RASopathy point-based PS4 framework.
PM1
This missense change affects residue 65, which is outside the KRAS RASopathy VCEP PM1 domains: P-loop amino acids 10-17, Switch I amino acids 25-40, Switch II amino acids 57-64, and SAK amino acids 145-156.
PM5
The retrieved evidence did not establish a different pathogenic or likely pathogenic amino acid change at the same codon, so PM5 was not applied.
PM6
No probable de novo occurrence without confirmed parentage was identified in the retrieved evidence, so PM6 was not applied.
PP1
No segregation data were identified for this variant, so PP1 was not applied.
PP3
For KRAS missense variants, PP3 requires REVEL at least 0.7.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is below the BA1 stand-alone benign threshold of at least 0.05%.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is below the BS1 threshold of at least 0.025%.
BS2
No well-documented unaffected carriers or other point-based benign observation data were identified, so BS2 was not applied.
BS4
No non-segregation data were identified, so BS4 was not applied.
BP2
No evidence of an alternative molecular cause in the same gene or qualifying phase information was identified, so BP2 was not applied.
BP4
For KRAS missense variants, BP4 requires REVEL 0.3 or lower.
BP5
No alternative molecular diagnosis or phenotype-based negative point evidence was identified, so BP5 was not applied.
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
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 Uncertain significance (1 clinical laboratory) and as Pathogenic (1 clinical laboratory) and as Likely 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 = 0.6. BayesDel score = 0.0836572.
Functional
Likely Oncogenic
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KRAS, a GTPase which functions as an upstream regulator of the MAPK pathway, is frequently mutated in various cancer types including lung, colorectal
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; COSV55620918, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links