Analysis in progress
Initialising…
0%
complete
This report is still being assembled — sections appear as each stage finishes. It isn't final yet.
KRAS
Final classification
VUS
PM2PP3
KRAS
c.57G>T
p.Leu19Phe
missense · exon 2
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 changes drive many cancers and germline alterations cause RASopathies such as Noonan syndrome, but this variant remains a VUS: it has only been reported as a somatic colorectal-tumor mutation, is absent from population databases, and meets only PM2 and PP3 at supporting strength. Additional germline or functional evidence would be needed to establish its clinical significance.

Transcript
NM_033360.2
HGVS · transcript:coding
NM_033360.2:c.57G>T
GRCh38
chr12:25245328 C>A
GRCh37
chr12:25398262 C>A
Basis Under the KRAS RASopathy VCEP v2.3 framework, only PM2 (Supporting) and PP3 (Supporting) are met; two supporting-strength criteria satisfy no combination rule, so the variant remains a VUS. ▾
Under the KRAS RASopathy VCEP v2.3 framework, only PM2 (Supporting) and PP3 (Supporting) are met; two supporting-strength criteria satisfy no combination rule, so the variant remains a VUS.
Classification rationale
PM2PP3 VUS
KRAS c.57G>T missense · exon 2

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. PP3 (Supporting): REVEL 0.797 exceeds the VCEP's >=0.7 missense threshold. VUS: with only PM2 and PP3 at supporting strength, no KRAS VCEP combination rule is satisfied.

PM2 + PP3 → VUS
Gene diagram · NM_033360.2 · variants mapped to exon structure
KRAS NM_033360.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 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): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, as required by the KRAS VCEP.
The KRAS VCEP PM2 rule is Supporting when the variant is absent from controls in gnomAD.The variant is explicitly reported absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
✓
PP3 supporting Pathogenic
Met (Supporting): REVEL 0.797 exceeds the VCEP's >=0.7 missense threshold.
ClinGen RASopathy VCEP KRAS specification v2.3 (cspec) defines PP3 for missense variants as REVEL >= 0.7, Supporting strength.Local REVEL predictor lookup (revel) returns a score of 0.797 for NM_033360.2:c.57G>T, which is >= 0.7, satisfying the VCEP PP3 threshold.
cspec ↗
Assessed · not applied · 6 not met · 11 not assessed
Pathogenic
PS1 Not assessed: no established pathogenic variant producing the identical p.Leu19Phe amino-acid change is documented.
PS2 Not assessed: the only reported occurrence is somatic in colorectal tumors, with no germline proband or parental testing to establish a de novo event.
PS3 Not assessed: no VCEP-approved functional assay result (e.g., RAS-GTP loading, MEK/ERK activation) exists for this variant.
PS4 Not assessed: no germline RASopathy case-control or phenotype data exist; only somatic colorectal-tumor cases were reported.
PM1 Not met: codon 19 falls outside the VCEP's critical functional domains (P-loop AA 10-17, Switch I, Switch II, SAK).
PM5 Not assessed: no established pathogenic amino-acid substitution at codon 19 is documented in the available evidence.
PM6 Not assessed: no presumed de novo germline occurrence without parental testing is documented; only a somatic tumor report exists.
PP1 Not assessed: no familial segregation data are available; the only report is a somatic tumor study.
PP5 Not met: no ClinVar expert-panel classification exists; the only laboratory submission is zero-star and ineligible.
Benign
BA1 Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, below the 0.05% benign threshold.
BS1 Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, below the 0.025% threshold.
BS2 Not assessed: no healthy adult carriers of this variant are documented, so carrier phenotype and penetrance are unknown.
BS4 Not assessed: no informative meiosis shows the variant not segregating with disease; only somatic tumor data exist.
BP2 Not assessed: no alternative molecular cause of a RASopathy in KRAS is documented.
BP4 Not met: REVEL 0.797 is well above the VCEP's BP4 threshold of <=0.3.
BP5 Not assessed: no alternative molecular cause in another gene or RASopathy phenotype data are available.
BP6 Not met: no ClinVar expert-panel benign classification exists for this variant.
N/A · 9 PVS1 · PM3 · PM4 · PP2 · PP4 · BS3 · BP1 · BP3 · 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 has been reported in ClinVar as Likely pathogenic (1 clinical laboratory). (ClinVarID = 376034)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.797. BayesDel score = 0.33595.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55502103, n = 30 times).
Hotspots
This variant lies 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 · 7 PMIDs not cited in assessment
17150185 ↗ Characterization of a novel oncogenic K-ras mutation in colon cancer. ONCOKB
20147967 ↗ Activating K-Ras mutations outwith 'hotspot' codons in sporadic colorectal tumou ONCOKB
28572459 ↗ AACR Project GENIE: Powering Precision Medicine through an International Consort ONCOKB
22918138 ↗ Opportunities and challenges associated with clinical diagnostic genome sequencing: a report of the Association for Molecular Pathology. CLINVAR
23619274 ↗ American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders. CLINVAR
34117033 ↗ Clinical and Functional Characterization of Atypical KRAS/NRAS Mutations in Metastatic Colorectal Cancer. CLINVAR
34131312 ↗ Chromosomal microarray analysis, including constitutional and neoplastic disease applications, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG). CLINVAR