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KRAS
Final classification
VUS
PM2BP1
KRAS
c.292G>T
p.Glu98Ter
nonsense · exon 4
Gene context NCBI Gene ↗ OncoKB ↗

KRAS encodes a small GTPase in the RAS family that cycles between active and inactive states to regulate cell growth and signaling through pathways such as MAPK/ERK and PI3K/AKT/mTOR. Activating changes in KRAS are common drivers of many cancers, including pancreatic, colorectal, and lung cancers, where they promote uncontrolled cell proliferation. Germline alterations in KRAS also cause developmental disorders such as Noonan syndrome and cardio-facio-cutaneous syndrome, which carry an increased predisposition to cancer.

This variant

KRAS activating missense changes drive many cancers and cause RASopathies such as Noonan syndrome, but this nonsense variant truncates the protein instead of activating it. It is absent from population databases, yet no clinical or functional evidence links it to disease. The variant is therefore classified as a variant of uncertain significance (VUS).

Transcript
NM_033360.4
HGVS · transcript:coding
NM_033360.4:c.292G>T
GRCh38
chr12:25225772 C>A
GRCh37
chr12:25378706 C>A
Basis VUS: only PM2 (Supporting, absent from gnomAD) and BP1 (Supporting, truncating variant in a gain-of-function gene) were met; no pathogenic or benign rule is satisfied. ▾
VUS: only PM2 (Supporting, absent from gnomAD) and BP1 (Supporting, truncating variant in a gain-of-function gene) were met; no pathogenic or benign rule is satisfied.
Classification rationale
PM2 BP1 VUS
KRAS c.292G>T nonsense · exon 4

PM2 (Supporting): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. 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. PM2 and BP1 at supporting strength satisfy no pathogenic or benign combination rule, so the variant is classified as VUS.

PM2 + BP1 → VUS
Gene diagram · NM_033360.4 · variants mapped to exon structure
KRAS NM_033360.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 12 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 · 2
Strength Supporting Moderate Strong Very strong
✓
PM2 supporting Pathogenic
Met (Supporting): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.
The KRAS RASopathy VCEP v2.3 PM2 rule assigns Supporting strength when the variant is absent from controls (gnomAD).Direct variant queries reported NM_033360.4:c.292G>T / GRCh37 12-25378706-C-A absent from gnomAD v2.1 and GRCh38 chr12-25225772-C-A absent from gnomAD v4.1; gnomAD-Canada v1.0 also reported absence.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
✓
BP1 supporting review Benign
Met (Supporting): p.(Glu98Ter) truncates the protein in KRAS, a gain-of-function disease gene without established loss-of-function correlation.
cSpec (KRAS RASopathy VCEP v2.3) BP1 rule: 'Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant ... in genes without established LOF correlation to disease.'cSpec (KRAS RASopathy VCEP v2.3) marks PVS1 'Not Applicable' for KRAS, consistent with a GOF-only disease mechanism and absence of an established LOF-disease correlation for this gene within the spec.OncoKB variant page for KRAS E98* records biological-effect context as 'Likely Loss-of-function', consistent with this nonsense variant acting through loss rather than gain of function.
cspec ↗oncokb ↗
Assessed · not applied · 3 not met · 9 not assessed
Pathogenic
PS2 Not assessed: no affected proband with parental testing is documented, so de novo occurrence cannot be confirmed.
PS3 Not assessed: no VCEP-approved functional assay (RAS, MEK, or ERK activation) results were available for this variant.
PS4 Not assessed: no germline RASopathy case series or proband counts were available to establish enrichment.
PM1 Not met: residue 98 falls outside the four critical domains (P-loop, Switch I, Switch II, SAK) defined by the VCEP.
PM6 Not assessed: no proband with untested parents is documented, so assumed de novo occurrence cannot be established.
PP1 Not assessed: no family segregation data or informative meioses were documented for this variant.
Benign
BA1 Not met: the variant is absent from gnomAD, so the >=0.05% frequency threshold for BA1 cannot be reached.
BS1 Not met: the variant is absent from gnomAD, so the >=0.025% frequency threshold for BS1 cannot be reached.
BS2 Not assessed: no observation of the variant in a healthy individual was documented.
BS4 Not assessed: no informative relative in whom the variant fails to segregate with disease was documented.
BP2 Not assessed: no affected-proband or phase data were available for the VCEP's BP2 point-based evidence.
BP5 Not assessed: no phenotype or alternate molecular diagnosis was available for BP5 point scoring.
N/A · 14 PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · PP3 · PP4 · PP5 · BS3 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). BayesDel score = 0.655873.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Likely Neutral
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Neutral.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55821941, n = 3 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 2 PMIDs not cited in assessment
28978093 ↗ Molecular characterization of circulating colorectal tumor cells defines genetic signatures for individualized cancer care. ONCOKB
34117033 ↗ Clinical and Functional Characterization of Atypical KRAS/NRAS Mutations in Metastatic Colorectal Cancer. ONCOKB