Variant classification summary

NM_033360.4:c.292G>T

KRAS · NP_203524.1:p.(Glu98Ter) · NM_033360.4

GRCh37: chr12:25378706 C>A · GRCh38: chr12:25225772 C>A

Gene: KRAS Transcript: NM_033360.4

Final call

VUS

PM2 supporting BP1 supporting

Variant details

Gene

KRAS

Transcript

NM_033360.4

Protein

NP_203524.1:p.(Glu98Ter)

gnomAD AF

ClinVar

OncoKB

Likely Neutral

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.

2

BP1 (Supporting): p.(Glu98Ter) is a truncating variant in KRAS, whose RASopathy mechanism is gain-of-function with no established loss-of-function disease correlation.

3

PM2 and BP1 at supporting strength satisfy no pathogenic or benign combination rule, so the variant is classified as VUS.

Final determination: No pathogenic or benign criteria-combination mainRule in the KRAS v2.3 cspec is satisfied by PM2 supporting + BP1 supporting alone, so the call is Uncertain Significance.

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	Not applicable: the RASopathy VCEP excludes PVS1 for KRAS, whose disease mechanism is gain-of-function rather than loss.	cspec
PS1	N/A	Not applicable: p.(Glu98Ter) is a nonsense change, and PS1 requires a missense change matching an established pathogenic variant.	cspec pm5_candidates
PS2	Not assessed	Not assessed: no affected proband with parental testing is documented, so de novo occurrence cannot be confirmed.	cspec
PS3	Not assessed	Not assessed: no VCEP-approved functional assay (RAS, MEK, or ERK activation) results were available for this variant.
PS4	Not assessed	Not assessed: no germline RASopathy case series or proband counts were available to establish enrichment.	cspec
PM1	Not met	Not met: residue 98 falls outside the four critical domains (P-loop, Switch I, Switch II, SAK) defined by the VCEP.	cspec
PM2	Met	Met (Supporting): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: the KRAS RASopathy VCEP specification does not apply PM3 to this gene.	cspec
PM4	N/A	Not applicable: a nonsense substitution is not an in-frame indel or stop-loss change, which PM4 requires.	cspec
PM5	N/A	Not applicable: p.(Glu98Ter) is a nonsense change, not a missense substitution, so the same-residue PM5 rule does not apply.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no proband with untested parents is documented, so assumed de novo occurrence cannot be established.	cspec
PP1	Not assessed	Not assessed: no family segregation data or informative meioses were documented for this variant.	cspec
PP2	N/A	Not applicable: the KRAS RASopathy VCEP explicitly marks PP2 as not applicable for this gene.	cspec
PP3	N/A	Not applicable: the REVEL rule covers only missense variants, and SpliceAI shows no splice impact (max delta 0.054).	cspec spliceai
PP4	N/A	Not applicable: the KRAS RASopathy VCEP explicitly marks PP4 as not applicable.	cspec
PP5	N/A	Not applicable: the VCEP marks PP5 not applicable, and the variant is absent from ClinVar.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD, so the >=0.05% frequency threshold for BA1 cannot be reached.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the variant is absent from gnomAD, so the >=0.025% frequency threshold for BS1 cannot be reached.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no observation of the variant in a healthy individual was documented.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	N/A	Not applicable: the KRAS RASopathy VCEP explicitly marks BS3 as not applicable.	cspec
BS4	Not assessed	Not assessed: no informative relative in whom the variant fails to segregate with disease was documented.	cspec
BP1	Met	Met (Supporting): p.(Glu98Ter) truncates the protein in KRAS, a gain-of-function disease gene without established loss-of-function correlation.	cspec oncokb
BP2	Not assessed	Not assessed: no affected-proband or phase data were available for the VCEP's BP2 point-based evidence.	cspec
BP3	N/A	Not applicable: the VCEP marks BP3 not applicable, and this is a nonsense substitution, not an in-frame indel.	cspec
BP4	N/A	Not applicable: the REVEL-based BP4 rule covers only missense variants, and BayesDel lacks a verified calibration threshold.	cspec spliceai bayesdel
BP5	Not assessed	Not assessed: no phenotype or alternate molecular diagnosis was available for BP5 point scoring.	cspec
BP6	N/A	Not applicable: the VCEP marks BP6 not applicable, and the variant is absent from ClinVar.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or intronic variants, not nonsense changes.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.