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
Final classification
Likely Pathogenic
PM1PM2PM5PP3PP5PS3
KRAS
c.178G>C
p.Gly60Arg
This variant
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 ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_004985.4 · variants mapped to exon structure
KRAS
NM_004985.4
Fetching transcript structure from UCSC…
Applied criteria · 6 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 · 6
Strength
Supporting
Moderate
Strong
Very strong
PS3
moderate
Pathogenic
In published functional studies, this variant increased the active GTP-bound KRAS fraction, showed marked GAP resistance, and increased downstream MEK and ERK phosphorylation relative to wild type, consistent with an activating effect. The RASopathy VCEP approved functional-study resource lists this variant as a pathogenic control in multiple approved assay types, which supports PS3 at moderate strength because two or more different approved assays were available.
PMID:20949621 reported increased GTP-bound KRASGAP resistanceand increased downstream signaling for G60R.
PM1
moderate
Pathogenic
This missense variant affects KRAS residue 60, which lies within the Switch II region (amino acids 57-64), a critical and well-established functional domain specified for PM1 in the KRAS RASopathy framework.
Residue 60 falls within KRAS Switch II (AA 57-64).KRAS RASopathy PM1 permits moderate strength for variants in Switch II.
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the KRAS RASopathy PM2 requirement for absence from population controls.
Absent from gnomAD v2.1.Absent from gnomAD v4.1.
PM5
moderate
review
Pathogenic
Different missense substitutions at KRAS codon 60 have been reported as pathogenic or likely pathogenic in ClinVar, including p.Gly60Val and p.Gly60Ser, which supports the classic same-residue PM5 rule at moderate strength for this novel amino acid change.
ClinVar same-codon comparators identified by tool review included KRAS p.Gly60Val (Pathogenic/Likely pathogenicmultiple submittersno conflicts) and KRAS p.Gly60Ser (Pathogenic
PP3
supporting
Pathogenic
Computational evidence supports a deleterious missense effect. The REVEL score is 0.938, which is above the KRAS RASopathy PP3 threshold of 0.7, and BayesDel is also positive at 0.539464. SpliceAI shows a possible splice effect with a max delta score of 0.25, but no RNA evidence was identified to establish a splice-based mechanism.
REVEL score 0.938.BayesDel score 0.539464.SpliceAI max delta score 0.25.
Assessed · not applied
· 4 not met · 8 not assessed
Pathogenic
PS1
No different nucleotide change producing the same amino acid substitution with established pathogenic classification was identified for KRAS p.Gly60Arg, so PS1 is not met.
PS2
Published affected-case evidence exists for this variant, but no directly confirmed de novo occurrence with sufficient parental confirmation and phenotype detail was verified from the reviewed sources, so PS2 was not assessed.
PS4
This variant has been reported in affected individuals and is classified as pathogenic by the ClinGen RASopathy expert panel in ClinVar, but the reviewed evidence did not establish the point total required by the KRAS RASopathy PS4 framework, so PS4 was not assessed.
PM6
Affected-case reports were identified in the literature and ClinVar, but no directly verified assumed de novo occurrence suitable for PM6 point assignment was confirmed from the reviewed evidence.
PP1
No informative familial segregation data were identified for this variant, so PP1 was not assessed.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the population frequency is below the KRAS RASopathy BA1 threshold of 0.05% and BA1 is not met.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the population frequency is below the KRAS RASopathy BS1 threshold of 0.025% and BS1 is not met.
BS2
No confirmed unaffected adult carriers or point-based BS2 evidence were identified, so BS2 was not assessed.
BS4
No informative non-segregation data were identified for this variant, so BS4 was not assessed.
BP2
No phased second pathogenic variant in KRAS and no point-based evidence for an alternative molecular cause in the same gene were identified, so BP2 was not assessed.
BP4
Available computational evidence does not support a benign missense effect.
BP5
No confirmed alternative molecular diagnosis or phenotype-based negative point evidence was identified, so BP5 was not assessed.
N/A · 10
PVS1 · PM3 · PM4 · PP2 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7
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. 12 further PMIDs triaged but not cited — see Sources & references.
Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders.
Found
reported increased GTP-bound KRAS GAP resistance and increased downstream signaling for G60R.
Applied to
→PS3
moderate
Sources & reference links
Triaged references · 12 PMIDs not cited in assessment
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