Variant classification summary

NM_001369786.1:c.194G>T

KRAS · NP_001356715.1:p.(Ser65Ile) · NM_001369786.1

GRCh37: chr12:25380264 C>A · GRCh38: chr12:25227330 C>A

Gene: KRAS Transcript: NM_001369786.1

Final call

VUS

PM2 supporting PP5 supporting

Variant details

Gene

KRAS

Transcript

NM_001369786.1

Protein

NP_001356715.1:p.(Ser65Ile)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting PM2 at supporting strength under the KRAS RASopathy specification.

3

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.

4

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.

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
PVS1	N/A	This 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.	cspec pvs1_variant_assessment
PS1	Not assessed	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.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence with sufficient parental testing and phenotype detail was identified, so PS2 was not applied.	cspec
PS3	Not assessed	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.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies oncokb
PS4	Not assessed	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.	cspec clinvar
PM1	Not met	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.	cspec
PM2	Met	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.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the KRAS RASopathy specification.	cspec
PM4	N/A	This is a missense substitution and does not cause an in-frame insertion, in-frame deletion, or stop-loss change, so PM4 is not applicable.	cspec
PM5	Not assessed	The retrieved evidence did not establish a different pathogenic or likely pathogenic amino acid change at the same codon, so PM5 was not applied.	cspec clinvar
PM6	Not assessed	No probable de novo occurrence without confirmed parentage was identified in the retrieved evidence, so PM6 was not applied.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not applied.	cspec
PP2	N/A	PP2 is not applicable in the KRAS RASopathy specification.	cspec
PP3	Not met	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.	cspec revel spliceai bayesdel
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 Likely pathogenic.	cspec clinvar
BA1	Not met	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.	cspec gnomad_v2 gnomad_v4
BS1	Not met	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.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No well-documented unaffected carriers or other point-based benign observation data were identified, so BS2 was not applied.	cspec
BS3	N/A	BS3 is not applicable in the KRAS RASopathy specification.	cspec
BS4	Not assessed	No non-segregation data were identified, so BS4 was not applied.	cspec
BP1	N/A	BP1 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.	cspec
BP2	Not assessed	No evidence of an alternative molecular cause in the same gene or qualifying phase information was identified, so BP2 was not applied.	cspec
BP3	N/A	BP3 is not applicable in the KRAS RASopathy specification.	cspec
BP4	Not met	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.	cspec revel spliceai bayesdel
BP5	Not assessed	No alternative molecular diagnosis or phenotype-based negative point evidence was identified, so BP5 was not applied.	cspec
BP6	N/A	BP6 is not applicable in this VCEP framework and was not used.	cspec
BP7	N/A	This is not a synonymous, intronic, or non-coding variant, so BP7 is not applicable.	cspec spliceai

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