NM_001369786.1:c.65A>G

KRAS · NP_001356715.1:p.(Gln22Arg) · NM_001369786.1

GRCh37: chr12:25398254 T>C · GRCh38: chr12:25245320 T>C

Gene: KRAS Transcript: NM_001369786.1

Final call

VUS

PM2 supporting PM5 moderate PP3 supporting PP5 supporting

Variant details

Gene

KRAS

Transcript

NM_001369786.1

Protein

NP_001356715.1:p.(Gln22Arg)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
BA1	Not met	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.	gnomad_v2 gnomad_v4 cspec
BP1	N/A	This 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.	cspec
BP2	Not assessed	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.	cspec
BP3	N/A	BP3 is not applicable in the KRAS RASopathy specification because no known benign repetitive regions are defined for this gene.	cspec
BP4	Not met	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.	revel spliceai cspec
BP5	Not assessed	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.	cspec
BP6	N/A	BP6 is not applicable in the KRAS RASopathy specification.	cspec
BP7	N/A	This 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.	cspec spliceai
BS1	Not met	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.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	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.	cspec
BS3	N/A	BS3 is not applicable in the KRAS RASopathy specification.	cspec
BS4	Not assessed	No family data were identified showing lack of segregation of this variant with disease, so BS4 was not assessed.	cspec
PM1	Not met	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.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Met	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.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable in the KRAS RASopathy specification.	cspec
PM4	N/A	This variant is a missense substitution and does not change protein length, so PM4 for protein length changes is not applicable.	cspec
PM5	Met	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 cspec
PM6	Not assessed	No report was identified showing this variant as an assumed de novo occurrence without full parental confirmation, so PM6 was not assessed.	cspec
PP1	Not assessed	No segregation data were identified for this variant in affected relatives, so PP1 was not assessed.	cspec
PP2	N/A	PP2 is not applicable in the KRAS RASopathy specification.	cspec
PP3	Met	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 spliceai bayesdel cspec
PP4	N/A	PP4 is not applicable in the KRAS RASopathy specification.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
PS1	Not met	No separate pathogenic variant producing the same amino acid change p.Gln22Arg by a different nucleotide substitution was identified, so PS1 is not met.	clinvar cspec
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified for this exact variant, so PS2 was not assessed.	cspec
PS3	Not assessed	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.	PMID:20949621 vcep_svi_rasopathy_vcep_v2_approved_functional_studies cspec
PS4	Not assessed	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.	clinvar cspec
PVS1	N/A	The 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.	cspec pvs1_gene_context pvs1_variant_assessment

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