About KRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KRAS c.65A>G, p.(Gln22Arg)
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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1. Under the KRAS RASopathy specification, absence from gnomAD supports PM2 at supporting strength.
PM5Moderate
PM5 · moderate
Different missense changes at the same KRAS codon 22 have already been reported in ClinVar with pathogenic or likely pathogenic classifications, including p.Gln22Glu, p.Gln22Lys, and p.Gln22Leu. This supports PM5 at moderate strength for a novel missense change at the same codon. The stronger PM5 level was not assigned because the currently reviewed evidence did not document at least 5 probands across at least 2 different pathogenic or likely pathogenic codon 22 substitutions.
PP3Supporting
PP3 · supporting
For KRAS missense variants, PP3 is met when REVEL is at least 0.7. The REVEL score for this variant is 0.749, which is above that threshold. SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, and the BayesDel score is 0.273188. Overall, the available computational evidence supports a damaging missense effect rather than a splicing mechanism, so PP3 is met at supporting strength.
PP5Supporting
PP5 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as 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, PM5 moderate, PP3 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.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
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 lies 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: 4 met · 5 not met · 9 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 NM_001369786.1:c.65A>G (p.Gln22Arg, p.Q22R) variant has been observed in somatic cancers in COSMIC (3 occurrences) and has been reported in ClinVar as pathogenic, including expert-panel review by the ClinGen RASopathy Variant Curation Expert Panel.
Different missense changes at the same KRAS codon 22, including p.Gln22Glu, p.Gln22Lys, and p.Gln22Leu, have also been reported in ClinVar as pathogenic or likely pathogenic, supporting PM5 at moderate strength.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2 at supporting strength and is below the KRAS benign frequency thresholds for BS1 and BA1.
Published KRAS functional studies included p.Gln22Arg among germline KRAS variants with abnormal biochemical or signaling properties, but the currently reviewed RASopathy VCEP functional-study matrix did not clearly establish a qualifying approved-assay count for PS3 assignment.
Computational evidence supports a damaging missense effect, with REVEL 0.749 meeting the KRAS PP3 threshold of at least 0.7, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01; the BayesDel score is 0.273188.
No criteria match.
Met · 4
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1. Under the KRAS RASopathy specification, absence from gnomAD supports PM2 at supporting strength. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
PM5 ModerateDifferent missense changes at the same KRAS codon 22 have already been reported in ClinVar with pathogenic or likely pathogenic classifications, including p.Gln22Glu, p.Gln22Lys, and p.Gln22Leu. This supports PM5 at moderate strength for a novel missense change at the same codon. The stronger PM5 level was not assigned because the currently reviewed evidence did not document at least 5 probands across at least 2 different pathogenic or likely pathogenic codon 22 substitutions. Details ▾Hide ▴
Rule
1 pathogenic or likely pathogenic residue change at the same codon.
Evidence considered
- ClinVar codon 22 missense variants include Q22E (Pathogenic)
- Q22K (Pathogenic/Likely pathogenic)
- and Q22L (Likely pathogenic)
- KRAS PM5 moderate requires one pathogenic or likely pathogenic residue change at the same codon
Still missing
- Direct proband counts across codon 22 pathogenic or likely pathogenic substitutions if considering PM5 strong
Sources
PP3 SupportingFor KRAS missense variants, PP3 is met when REVEL is at least 0.7. The REVEL score for this variant is 0.749, which is above that threshold. SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, and the BayesDel score is 0.273188. Overall, the available computational evidence supports a damaging missense effect rather than a splicing mechanism, so PP3 is met at supporting strength. Details ▾Hide ▴
Rule
For missense variants: REVEL >=0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.749
- SpliceAI max delta 0.01
- BayesDel 0.273188
- KRAS PP3 threshold REVEL >=0.7
Sources
Not met · 5 · evaluated, threshold not reached
PS1 No separate pathogenic variant producing the same amino acid change p.Gln22Arg by a different nucleotide substitution was identified, so PS1 is not met. Details ▾Hide ▴
PM1 KRAS RASopathy PM1 is limited to the defined functional domains P-loop (amino acids 10-17), Switch I (25-40), Switch II (57-64), and SAK (145-156). This variant affects codon 22, which is outside those defined PM1 domains, so PM1 is not met. Details ▾Hide ▴
Rule
Applicable only to critical and well-established functional domains: P-loop (AA 10-17), SW1 (AA 25-40), SW2 (AA 57-64), SAK (AA 145-156).
Evidence considered
- Variant affects codon 22
- KRAS PM1 domains are 10-17
- 25-40
- 57-64
- and 145-156
Sources
cspec ↗vcep_alignment_with_pm1_domains_pptx
BA1 This missense variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the KRAS RASopathy BA1 threshold of at least 0.05%, so BA1 is not met. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency >=0.05%.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- KRAS RASopathy BA1 threshold is gnomAD filtering allele frequency >=0.05%
Sources
BS1 This missense variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the KRAS RASopathy BS1 threshold of at least 0.025%, so BS1 is not met. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency >=0.025%.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- KRAS RASopathy BS1 threshold is gnomAD filtering allele frequency >=0.025%
Sources
BP4 For KRAS missense variants, BP4 requires REVEL 0.3 or lower. The REVEL score is 0.749, which is above this benign threshold, so BP4 is not met. SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01, but that does not override the missense predictor threshold. Details ▾Hide ▴
Rule
For missense variants: REVEL <=0.3.
Evidence considered
- REVEL 0.749
- SpliceAI max delta 0.01
- KRAS BP4 threshold REVEL <=0.3
Sources
Not assessed · 9 · no assessment recorded
PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this exact variant, so PS2 was not assessed. Details ▾Hide ▴
Rule
Points-based confirmed de novo evidence with increasing strength.
Evidence considered
- No confirmed de novo evidence retrieved for this exact variant
Still missing
- Confirmed de novo case report with parental testing
Sources
PS3 Published functional studies included KRAS p.Gln22Arg and described abnormal KRAS biochemical or signaling properties in the broader set of germline KRAS variants, but the currently reviewed RASopathy VCEP functional-study matrix did not clearly establish a qualifying count of approved assays for this exact variant under the KRAS PS3 rule. PS3 was therefore not assessed pending direct assay-level confirmation. Details ▾Hide ▴
Rule
Moderate with two or more different approved assays; supporting with one approved assay.
Evidence considered
- PMID 20949621 evaluated p.Q22R among germline KRAS variants
- VCEP functional-study workbook reviewed for approved assay support
Still missing
- Direct confirmation of the number of approved VCEP assays satisfied for p.Gln22Arg
Sources
PS4 This variant has been observed in somatic cancers and is present in ClinVar, but the currently reviewed evidence did not provide the case-count and points-based germline affected-individual data required by the KRAS RASopathy PS4 rule. PS4 was therefore not assessed. Details ▾Hide ▴
Rule
Points-based enrichment in affected individuals.
Evidence considered
- COSMIC reports 3 somatic occurrences
- ClinVar reports pathogenic expert-panel classification
- No germline PS4 points calculation retrieved
Still missing
- Exact germline affected proband counts and PS4 points calculation
Sources
PM6 No report was identified showing this variant as an assumed de novo occurrence without full parental confirmation, so PM6 was not assessed. Details ▾Hide ▴
Rule
Points-based de novo evidence without full confirmation.
Evidence considered
- No apparently de novo report retrieved for this exact variant
Still missing
- Patient-level apparently de novo report for this exact variant
Sources
PP1 No segregation data were identified for this variant in affected relatives, so PP1 was not assessed. Details ▾Hide ▴
Rule
Segregation in affected relatives with increasing strength by informative meioses.
Evidence considered
- No family segregation evidence retrieved
Still missing
- Informative segregation data
Sources
BS2 No evidence was identified showing this variant in a sufficient number of unaffected individuals for the KRAS RASopathy BS2 points system, so BS2 was not assessed. Details ▾Hide ▴
Rule
Points-based benign evidence from observations in unaffected individuals.
Evidence considered
- No unaffected-carrier evidence retrieved
Still missing
- Unaffected carrier data with phenotype assessment
Sources
BS4 No family data were identified showing lack of segregation of this variant with disease, so BS4 was not assessed. Details ▾Hide ▴
Rule
Requires one informative meiosis showing non-segregation.
Evidence considered
- No non-segregation evidence retrieved
Still missing
- Informative non-segregation data
Sources
BP2 No phase data or alternative molecular diagnosis data were identified to show this variant occurring in trans with a pathogenic variant or in a context that would support a benign interpretation, so BP2 was not assessed. Details ▾Hide ▴
Rule
Points-based benign evidence for phase/alternative explanation.
Evidence considered
- No case-specific phase evidence retrieved
Still missing
- Case-level phase data
- Documented alternative molecular diagnosis if present
Sources
BP5 No independent molecular diagnosis or phenotype explanation was identified that would account for the clinical presentation apart from this variant, so BP5 was not assessed. Details ▾Hide ▴
Rule
Points-based benign evidence for an alternative molecular cause of disease.
Evidence considered
- No alternative molecular explanation retrieved
Still missing
- Case-level alternate diagnosis data
- Phenotype correlation if another causative variant exists
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThe KRAS RASopathy specification marks PVS1 as not applicable for this framework, and this variant is a missense substitution rather than a null variant. The variant-specific PVS1 scaffold also states that this change does not fall into the generic nonsense, frameshift, or canonical splice-site categories. Details ▾Hide ▴
Evidence considered
- KRAS PVS1 marked not applicable in the RASopathy specification
- Variant is missense p.(Gln22Arg)
- Generic PVS1 scaffold does not apply to this variant type
Sources
PM3 N/APM3 is not applicable in the KRAS RASopathy specification. Details ▾Hide ▴
PM4 N/AThis variant is a missense substitution and does not change protein length, so PM4 for protein length changes is not applicable. Details ▾Hide ▴
Rule
Protein length changes outside repetitive regions.
Evidence considered
- Variant consequence is missense p.(Gln22Arg)
Sources
PP2 N/APP2 is not applicable in the KRAS RASopathy specification. Details ▾Hide ▴
PP4 N/APP4 is not applicable in the KRAS RASopathy specification. Details ▾Hide ▴
BS3 N/ABS3 is not applicable in the KRAS RASopathy specification. Details ▾Hide ▴
BP1 N/AThis is a missense variant, not a truncating variant. The KRAS RASopathy BP1 specification is intended for truncating variants in genes without an established loss-of-function disease correlation, so BP1 is not applicable. Details ▾Hide ▴
Rule
Use BP1 for truncating variants in genes without established LOF correlation to disease.
Evidence considered
- Variant consequence is missense p.(Gln22Arg)
- KRAS BP1 rule is written for truncating variants
Sources
BP3 N/ABP3 is not applicable in the KRAS RASopathy specification because no known benign repetitive regions are defined for this gene. Details ▾Hide ▴
BP6 N/ABP6 is not applicable in the KRAS RASopathy specification. Details ▾Hide ▴
BP7 N/AThis variant is missense rather than synonymous or intronic, so the KRAS RASopathy BP7 rule for synonymous or non-coding variants with no predicted splice impact does not apply. Details ▾Hide ▴
Rule
Synonymous or non-coding variant with no predicted splice impact and low conservation.
Evidence considered
- Variant consequence is missense p.(Gln22Arg)
- BP7 is a synonymous/non-coding rule
Sources
Identifiers
- Gene
- KRAS
- Transcript
- NM_001369786.1
- Coding (HGVS c.)
- NM_001369786.1:c.65A>G
- Protein (HGVS p.)
- NP_001356715.1:p.(Gln22Arg)
- GRCh38
- chr12:25245320 T>C
- GRCh37
- chr12:25398254 T>C
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 SupportingFor KRAS missense variants, PP3 is met when REVEL is at least 0.7. The REVEL score for this variant is 0.749, which is above that threshold. SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, and the BayesDel score is 0.273188. Overall, the available computational evidence supports a damaging missense effect rather than a splicing mechanism, so PP3 is met at supporting strength. Details ▾Hide ▴
Rule
For missense variants: REVEL >=0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.749
- SpliceAI max delta 0.01
- BayesDel 0.273188
- KRAS PP3 threshold REVEL >=0.7
Sources
BP4 For KRAS missense variants, BP4 requires REVEL 0.3 or lower. The REVEL score is 0.749, which is above this benign threshold, so BP4 is not met. SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01, but that does not override the missense predictor threshold. Details ▾Hide ▴
Rule
For missense variants: REVEL <=0.3.
Evidence considered
- REVEL 0.749
- SpliceAI max delta 0.01
- KRAS BP4 threshold REVEL <=0.3
Sources
BP7 N/AThis variant is missense rather than synonymous or intronic, so the KRAS RASopathy BP7 rule for synonymous or non-coding variants with no predicted splice impact does not apply. Details ▾Hide ▴
Rule
Synonymous or non-coding variant with no predicted splice impact and low conservation.
Evidence considered
- Variant consequence is missense p.(Gln22Arg)
- BP7 is a synonymous/non-coding rule
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.749. BayesDel score = 0.273188.
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/40452/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-25398254-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-25245320-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001369786.1%3Ac.6…
- OncoKB ↗www.oncokb.org/gene/KRAS/Q22R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=108041746
- 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 Pathogenic (12 clinical laboratories) 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 = 0.749. BayesDel score = 0.273188.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55525137, n = 3 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.