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LYFE SCIENCES
Project: HERA
NM_001369786.1:c.194G>T
p.Ser65Ile  ·  KRAS
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Classification rationale
1

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.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting PM2 at supporting strength under the KRAS RASopathy specification.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

oncokb ↗
4

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.

cspec ↗ spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.6. BayesDel score = 0.0836572.
SpliceAI ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueS65
Hotspots ↗