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KRAS
Final classification
VUS
KRAS c.194G>T · p.Ser65Ile
KRAS

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.

Gene
KRAS
Transcript
NM_001369786.1
HGVS · transcript:coding
NM_001369786.1:c.194G>T
Consequence
N/A
GRCh38
chr12:25227330 C>A
GRCh37
chr12:25380264 C>A
Basis 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.
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

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

PM2 + PP5 VUS
3 vcep_svi_rasopathy_vcep_v2_approved_functional_studiesoncokb ↗
4 cspec ↗revelbayesdelspliceai ↗
Gene diagram · NM_001369786.1 · variants mapped to exon structure
KRAS NM_001369786.1
Fetching transcript structure from UCSC…
Applied criteria · 2 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 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      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
      Not observed in any ancestry group.
      gnomAD v2.1
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      ClinVar screenshot
      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).
      SpliceAI screenshot
      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 / OncoKB screenshot
      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
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      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
      8Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots