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.1 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.2 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 BA1.3 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.4 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 0.273188.5
Final classification
VUS
PM2PM5PP3PP5
KRAS
c.65A>G
p.Gln22Arg
This variant
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.
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.
Classification rationale
PM2PM5PP3PP5
VUS
KRAS c.65A>G
PM2 + PM5 + PP3 + PP5
→
VUS
4
PMID:20949621 ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studiescspec ↗
5
revelspliceai ↗bayesdelcspec ↗
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 · 4 applied · 14 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 · 4
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
review
Pathogenic
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.
Absent from gnomAD v2.1Absent from gnomAD v4.1
PM5
moderate
review
Pathogenic
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.
ClinVar codon 22 missense variants include Q22E (Pathogenic)Q22K (Pathogenic/Likely pathogenic)and Q22L (Likely pathogenic)
PP3
supporting
review
Pathogenic
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.
REVEL 0.749SpliceAI max delta 0.01BayesDel 0.273188
Assessed · not applied
· 5 not met · 9 not assessed
Pathogenic
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.
PS2
No confirmed de novo occurrence with verified maternity and paternity was identified for this exact variant, so PS2 was not assessed.
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.
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.
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).
PM6
No report was identified showing this variant as an assumed de novo occurrence without full parental confirmation, so PM6 was not assessed.
PP1
No segregation data were identified for this variant in affected relatives, so PP1 was not assessed.
Benign
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.
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.
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.
BS4
No family data were identified showing lack of segregation of this variant with disease, so BS4 was not assessed.
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.
BP4
For KRAS missense variants, BP4 requires REVEL 0.3 or lower.
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.
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 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
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55525137, n = 3 times).
Hotspots
This variant lies in a statistically significant hotspot.
Sources & reference links