The KRAS c.178G>C (p.Gly60Arg) variant has been observed in somatic cancers in COSMIC and has been reported in ClinVar, where it is classified as Pathogenic including review by the ClinGen RASopathy expert panel.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets.2 In a published functional study, this variant increased the active GTP-bound KRAS fraction, showed marked GAP resistance, and increased downstream MEK and ERK signaling relative to wild type, consistent with an activating effect; the RASopathy VCEP approved functional-study resource also supports use of multiple approved assay types for this variant.3 Computational evidence supports a damaging missense effect, with REVEL 0.938 above the KRAS PP3 threshold of 0.7 and a positive BayesDel score of 0.539464; SpliceAI shows a possible splice effect with a max delta score of 0.25, but no RNA evidence was identified.4
KRAS
Final classification
Likely Pathogenic
KRAS c.178G>C · p.Gly60Arg
KRAS
The KRAS c.178G>C (p.Gly60Arg) variant has been observed in somatic cancers in COSMIC and has been reported in ClinVar, where it is classified as Pathogenic including review by the ClinGen RASopathy expert panel.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule14 (2 Pathogenic.Moderate + Pathogenic.Supporting >=2) with applied criteria: PM1 moderate, PM2 supporting, PM5 moderate, PP3 supporting, PP5 supporting, PS3 moderate; maps to Likely Pathogenic.
Classification rationale
PM1PM2PM5PP3PP5PS3
Likely Pathogenic
KRAS c.178G>C
PM1 + PM2 + PM5 + PP3 + PP5 + PS3
→
Likely Pathogenic
3
PMID:20949621 ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
4
revelbayesdelspliceai ↗cspec ↗
Gene diagram
· NM_004985.4 · variants mapped to exon structure
KRAS
NM_004985.4
Fetching transcript structure from UCSC…
Applied criteria · 6 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (8 clinical laboratories) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 12586)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.25). REVEL score = 0.938. BayesDel score = 0.539464.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55690921, n = 1 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 13 further PMIDs triaged but not cited — see Sources & References.
PMID PMID:20949621
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links
Triaged references · 13 PMIDs not cited in assessment
20949621 ↗
Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders.
ONCOKB
24030381 ↗
Clinical and biological implications of driver mutations in myelodysplastic syndromes.
ONCOKB
19396835 ↗
Craniosynostosis in patients with Noonan syndrome caused by germline KRAS mutations.
CLINVAR
23652378 ↗
A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.
CLINVAR
24033266 ↗
A systematic approach to assessing the clinical significance of genetic variants.
CLINVAR
25626707 ↗
Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.
CLINVAR
25730230 ↗
Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.
CLINVAR
22947299 ↗
Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening.
CLINVAR
23037933 ↗
Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.
CLINVAR
23881473 ↗
Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors.
CLINVAR
24394680 ↗
Parental permission for pilot newborn screening research: guidelines from the NBSTRN.
CLINVAR
25173338 ↗
2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR