The KRAS c.173C>T (p.Thr58Ile, T58I) variant has been observed in somatic cancer literature and has also been reported in ClinVar as pathogenic, including expert panel review by the ClinGen RASopathy Variant Curation Expert Panel.1 This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at 1/1613990 alleles (AF 6.19583e-07; 0.00006%), which is far below the KRAS RASopathy VCEP benign frequency thresholds.2 In published functional studies, p.Thr58Ile showed defective intrinsic GTP hydrolysis, impaired responsiveness to GAP-mediated regulation, and abnormal downstream signaling; the RASopathy VCEP approved functional study set also includes this variant as a pathogenic or likely pathogenic control in multiple approved assay classes, supporting a gain-of-function effect.3 Computational evidence supports a deleterious missense effect, with REVEL 0.921 above the VCEP PP3 threshold of 0.7, BayesDel 0.42458, and SpliceAI showing no significant splice effect (max delta score 0.03).4
Final classification
VUS
PS3PM1PP3PP5
KRAS
c.173C>T
p.Thr58Ile
This variant
The KRAS c.173C>T (p.Thr58Ile, T58I) variant has been observed in somatic cancer literature and has also been reported in ClinVar as pathogenic, including expert panel review by the ClinGen RASopathy Variant Curation 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 was evaluated deterministically with applied criteria: PS3 moderate, PM1 moderate, PP3 supporting, PP5 supporting; no rule matched the adjudicated criteria.
Classification rationale
PS3PM1PP3PP5
VUS
KRAS c.173C>T
PS3 + PM1 + PP3 + PP5
→
VUS
3
PMID:16474405 ↗PMID:20949621 ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
4
cspec ↗revelbayesdelspliceai ↗
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 · 4 applied · 14 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 · 4
Strength
Supporting
Moderate
Strong
Very strong
PS3
moderate
review
Pathogenic
In VCEP-approved functional datasets, p.(Thr58Ile) appears as a pathogenic or likely pathogenic validation control in multiple approved assay classes, including RAS activation, MEK activation, and ERK activation assays. Published studies also showed defective intrinsic GTP hydrolysis, impaired GAP responsiveness, and deregulated downstream signaling, consistent with a gain-of-function effect.
VCEP-approved functional study spreadsheet lists T58I in multiple approved assay classesPMID 16474405 reports defective intrinsic GTP hydrolysisimpaired GAP responsiveness
PM1
moderate
review
Pathogenic
The p.(Thr58Ile) change lies in the KRAS Switch II region, which the KRAS RASopathy VCEP defines as a critical and well-established functional domain spanning amino acids 57-64. Codon 58 falls within this curated domain.
KRAS Switch II curated domain AA57-AA64Thr58 is within the Switch II domain
PP3
supporting
review
Pathogenic
Computational evidence supports a deleterious missense effect. The REVEL score is 0.921, which is above the KRAS RASopathy VCEP PP3 threshold of 0.7. BayesDel is also positive at 0.42458, and SpliceAI predicts no significant splice impact with a max delta score of 0.03, supporting a missense rather than splice-mediated mechanism.
REVEL 0.921BayesDel 0.42458SpliceAI max delta 0.03
Assessed · not applied
· 4 not met · 10 not assessed
Pathogenic
PS1
No evidence was identified here showing the same amino acid change, p.(Thr58Ile), from a different nucleotide change that is already established as pathogenic.
PS2
Published literature reports de novo KRAS mutations including p.(Thr58Ile), but the available evidence reviewed here does not provide enough detail on parental confirmation and phenotype point assignment to apply the RASopathy VCEP de novo scoring rule confidently.
PS4
This variant has been reported in affected individuals and is classified as pathogenic in ClinVar, but the reviewed evidence does not provide enough case counting and point assignment detail to apply the RASopathy VCEP PS4 scoring framework.
PM2
This variant is not absent from controls because it is present in gnomAD v4.1 at 1/1613990 alleles (AF 6.19583e-07; 0.00006%), although it is absent from gnomAD v2.1.
PM5
No reviewed evidence here established a different pathogenic or likely pathogenic amino acid change at codon 58 that would allow PM5 to be applied.
PM6
Published literature suggests de novo occurrence of p.(Thr58Ile), but the reviewed evidence does not provide enough detail to assign a de novo point total under the RASopathy VCEP PM6 framework.
PP1
No segregation data were identified to show cosegregation of this variant with disease in informative meioses.
Benign
BA1
The observed population frequency does not reach the BA1 threshold.
BS1
The observed population frequency does not reach the BS1 threshold.
BS2
No evidence was identified showing this variant in the number of unaffected individuals required for the RASopathy VCEP BS2 point system.
BS4
No nonsegregation data were identified for this variant.
BP2
No phase data or alternative molecular explanation data were identified to support BP2 scoring.
BP4
Computational evidence does not support a benign effect.
BP5
No alternative molecular diagnosis or phenotype explanation was identified that would support BP5 scoring.
N/A · 10
PVS1 · PM3 · PM4 · PP2 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.19583e-07; MAF= 0.00006%, 1/1613990 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 1.56245e-05; MAF= 0.00156%, 1/64002 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,613,990
0 hom
0 hom
European (Finnish) 1 / 64,002 |
0.0016% |
+ 9 not observed (Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
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 (5 clinical laboratories) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.921. BayesDel score = 0.42458.
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 does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55527371, n = 26 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Germline KRAS mutations cause Noonan syndrome.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
moderate
Germline KRAS mutations cause aberrant biochemical and physical properties leadi
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
moderate
Sources & reference links