About KRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KRAS c.194G>T, p.(Ser65Ile)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen KRAS VCEP v2.3.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
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.
PP5Supporting
PP5 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
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
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen KRAS VCEP v2.3.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 5 not met · 11 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting PM2 at supporting strength under the KRAS RASopathy specification.
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.
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.
No criteria match.
Met · 2
PM2 SupportingThis 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. Details ▾Hide ▴
Rule
PM2_Supporting: variant absent from controls (gnomAD).
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- VCEP PM2 threshold is absence from controls
Sources
Not met · 5 · evaluated, threshold not reached
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. Therefore, PM1 is not met. Details ▾Hide ▴
Rule
PM1 applies only to the specified KRAS functional domains and not to residues outside those boundaries.
Evidence considered
- Protein consequence p.(Ser65Ile)
- KRAS PM1 domains defined as 10-17
- 25-40
- 57-64
- and 145-156
- Residue 65 lies just outside Switch II
Sources
PP3 For KRAS missense variants, PP3 requires REVEL at least 0.7. This variant has REVEL 0.60, which is below that threshold. SpliceAI shows a maximum delta score of 0.01, indicating no predicted splice effect, and the available BayesDel score of 0.0836572 does not provide additional gene-specific support for PP3 under the KRAS VCEP rule. Details ▾Hide ▴
Rule
PP3_Supporting for missense variants requires REVEL >=0.7; splicing prediction must match disease mechanism when relevant.
Evidence considered
- REVEL 0.60
- PP3 threshold REVEL >=0.7
- SpliceAI max delta 0.01
- BayesDel 0.0836572
Sources
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%. BA1 is not met. Details ▾Hide ▴
Rule
BA1 requires gnomAD filtering allele frequency >=0.05%.
Evidence considered
- Variant absent from gnomAD v2.1
- Variant absent from gnomAD v4.1
- BA1 threshold >=0.05%
Sources
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%. BS1 is not met. Details ▾Hide ▴
Rule
BS1 requires gnomAD filtering allele frequency >=0.025%.
Evidence considered
- Variant absent from gnomAD v2.1
- Variant absent from gnomAD v4.1
- BS1 threshold >=0.025%
Sources
BP4 For KRAS missense variants, BP4 requires REVEL 0.3 or lower. This variant has REVEL 0.60, which is above the benign threshold. SpliceAI shows a maximum delta score of 0.01, indicating no predicted splice effect, but that does not overcome the missense REVEL threshold requirement, so BP4 is not met. Details ▾Hide ▴
Rule
BP4_Supporting for missense variants requires REVEL <=0.3.
Evidence considered
- REVEL 0.60
- BP4 threshold REVEL <=0.3
- SpliceAI max delta 0.01
- BayesDel 0.0836572
Sources
Not assessed · 11 · no assessment recorded
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. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- ClinVar record for p.(Ser65Ile) was reviewed
- No alternate nucleotide with the same amino acid change was documented in the retrieved evidence
Still missing
- A same-amino-acid pathogenic comparison variant was not identified in the retrieved evidence.
Sources
PS2 No confirmed de novo occurrence with sufficient parental testing and phenotype detail was identified, so PS2 was not applied. Details ▾Hide ▴
Rule
RASopathy VCEP point-based de novo scoring for confirmed de novo occurrences.
Evidence considered
- Exploratory review did not identify a confirmed de novo report
Still missing
- Parental testing status was not available.
- No confirmed de novo case with point-based evidence was identified.
Sources
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. Details ▾Hide ▴
Rule
One approved assay supports PS3_Supporting; two or more different approved assays support PS3_Moderate.
Evidence considered
- RASopathy VCEP approved functional assay framework reviewed
- OncoKB did not identify variant-specific reviewed functional evidence
Still missing
- No variant-specific approved assay result for p.(Ser65Ile) was identified.
- Direct review of any additional primary functional literature would be needed to support PS3.
Sources
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. Details ▾Hide ▴
Rule
RASopathy VCEP point-based affected-individual scoring.
Evidence considered
- ClinVar contains expert-panel and clinical-laboratory submissions
- RASopathy VCEP PS4 requires point-based case evidence
Still missing
- No scored affected-individual count was available.
- No case-control enrichment data were identified.
Sources
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. Details ▾Hide ▴
Rule
PM5 requires a different pathogenic or likely pathogenic missense change at the same codon; PM5_Strong requires two different changes observed in at least 5 probands.
Evidence considered
- Codon-level pathogenic comparator not established in the retrieved evidence
Still missing
- A same-codon pathogenic comparison variant was not identified in the retrieved evidence.
- Additional codon-level review would be needed to determine whether PM5 can be applied.
Sources
PM6 No probable de novo occurrence without confirmed parentage was identified in the retrieved evidence, so PM6 was not applied. Details ▾Hide ▴
Rule
RASopathy VCEP point-based de novo scoring for assumed de novo occurrences.
Evidence considered
- Exploratory review did not identify a probable de novo case
Still missing
- No inheritance report supporting assumed de novo occurrence was identified.
Sources
PP1 No segregation data were identified for this variant, so PP1 was not applied. Details ▾Hide ▴
Rule
PP1 requires segregation with disease, with strength based on informative meioses.
Evidence considered
- No segregation report identified
Still missing
- No pedigree data or informative meioses were available.
Sources
BS2 No well-documented unaffected carriers or other point-based benign observation data were identified, so BS2 was not applied. Details ▾Hide ▴
Rule
BS2 uses point-based benign observations under the KRAS RASopathy specification.
Evidence considered
- No benign observation dataset identified for this variant
Still missing
- No unaffected-carrier evidence was available.
Sources
BS4 No non-segregation data were identified, so BS4 was not applied. Details ▾Hide ▴
Rule
BS4 requires evidence that the variant does not segregate with disease.
Evidence considered
- No non-segregation report identified
Still missing
- No family data showing lack of segregation were available.
Sources
BP2 No evidence of an alternative molecular cause in the same gene or qualifying phase information was identified, so BP2 was not applied. Details ▾Hide ▴
Rule
BP2 uses point-based scoring for an alternative molecular explanation in the same gene.
Evidence considered
- No qualifying BP2 evidence identified
Still missing
- No same-gene alternative molecular explanation or phase data were available.
Sources
BP5 No alternative molecular diagnosis or phenotype-based negative point evidence was identified, so BP5 was not applied. Details ▾Hide ▴
Rule
BP5 uses point-based scoring for an alternative molecular explanation or phenotype inconsistency.
Evidence considered
- No qualifying BP5 evidence identified
Still missing
- No alternate molecular explanation or fully explanatory non-RASopathy diagnosis was available.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the KRAS RASopathy specification marks PVS1 as not applicable. The generic PVS1 scaffold also indicates that c.194G>T does not fall into a null-variant category such as nonsense, frameshift, or canonical splice-site change. Details ▾Hide ▴
Rule
PVS1 not applicable for this missense KRAS variant under the KRAS RASopathy specification.
Evidence considered
- Missense change p.(Ser65Ile)
- VCEP marks PVS1 not applicable
- Generic PVS1 scaffold does not place this variant in a null-variant bucket
Sources
cspec ↗pvs1_variant_assessment
PM3 N/APM3 is not applicable in the KRAS RASopathy specification. Details ▾Hide ▴
Rule
PM3 not applicable for this VCEP.
Evidence considered
- Criterion marked not applicable by KRAS RASopathy specification
Sources
PM4 N/AThis is a missense substitution and does not cause an in-frame insertion, in-frame deletion, or stop-loss change, so PM4 is not applicable. Details ▾Hide ▴
Rule
PM4 applies to protein length changes such as in-frame indels or stop-loss variants.
Evidence considered
- Single-nucleotide missense substitution p.(Ser65Ile)
Sources
PP2 N/APP2 is not applicable in the KRAS RASopathy specification. Details ▾Hide ▴
Rule
PP2 not applicable for this VCEP.
Evidence considered
- Criterion marked not applicable by KRAS RASopathy specification
Sources
PP4 N/APP4 is not applicable in the KRAS RASopathy specification. Details ▾Hide ▴
Rule
PP4 not applicable for this VCEP.
Evidence considered
- Criterion marked not applicable by KRAS RASopathy specification
Sources
BS3 N/ABS3 is not applicable in the KRAS RASopathy specification. Details ▾Hide ▴
Rule
BS3 not applicable for this VCEP.
Evidence considered
- Criterion marked not applicable by KRAS RASopathy specification
Sources
BP1 N/ABP1 in this KRAS RASopathy framework is intended for truncating loss-of-function variants in genes without established loss-of-function disease correlation. This variant is missense, so BP1 is not applicable. Details ▾Hide ▴
Rule
BP1 applies here to truncating variants, not missense substitutions.
Evidence considered
- Missense variant p.(Ser65Ile)
Sources
BP3 N/ABP3 is not applicable in the KRAS RASopathy specification. Details ▾Hide ▴
Rule
BP3 not applicable for this VCEP.
Evidence considered
- Criterion marked not applicable by KRAS RASopathy specification
Sources
BP6 N/ABP6 is not applicable in this VCEP framework and was not used. Details ▾Hide ▴
Rule
BP6 not for use in this VCEP.
Evidence considered
- Criterion marked not applicable by VCEP/ClinGen SVI policy
Sources
BP7 N/AThis is not a synonymous, intronic, or non-coding variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous, certain intronic, or non-coding variants with no predicted splice effect.
Evidence considered
- Missense substitution p.(Ser65Ile)
- SpliceAI max delta 0.01
Sources
Identifiers
- Gene
- KRAS
- Transcript
- NM_001369786.1
- Coding (HGVS c.)
- NM_001369786.1:c.194G>T
- Protein (HGVS p.)
- NP_001356715.1:p.(Ser65Ile)
- GRCh38
- chr12:25227330 C>A
- GRCh37
- chr12:25380264 C>A
Gene diagram
Every interpreted variant in KRAS, mapped onto the exon structure of NM_001369786.1. Select a row to find it on the plot.
KRASNM_001369786.1
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in KRAS
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 For KRAS missense variants, PP3 requires REVEL at least 0.7. This variant has REVEL 0.60, which is below that threshold. SpliceAI shows a maximum delta score of 0.01, indicating no predicted splice effect, and the available BayesDel score of 0.0836572 does not provide additional gene-specific support for PP3 under the KRAS VCEP rule. Details ▾Hide ▴
Rule
PP3_Supporting for missense variants requires REVEL >=0.7; splicing prediction must match disease mechanism when relevant.
Evidence considered
- REVEL 0.60
- PP3 threshold REVEL >=0.7
- SpliceAI max delta 0.01
- BayesDel 0.0836572
Sources
BP4 For KRAS missense variants, BP4 requires REVEL 0.3 or lower. This variant has REVEL 0.60, which is above the benign threshold. SpliceAI shows a maximum delta score of 0.01, indicating no predicted splice effect, but that does not overcome the missense REVEL threshold requirement, so BP4 is not met. Details ▾Hide ▴
Rule
BP4_Supporting for missense variants requires REVEL <=0.3.
Evidence considered
- REVEL 0.60
- BP4 threshold REVEL <=0.3
- SpliceAI max delta 0.01
- BayesDel 0.0836572
Sources
BP7 N/AThis is not a synonymous, intronic, or non-coding variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous, certain intronic, or non-coding variants with no predicted splice effect.
Evidence considered
- Missense substitution p.(Ser65Ile)
- SpliceAI max delta 0.01
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.6. BayesDel score = 0.0836572.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243114
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/438796/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-25380264-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-25227330-C-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001369786.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/KRAS/S65I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=108026942
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
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
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
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55620918, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.