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LYFE SCIENCES
Project: HERA
NM_004985.4:c.173C>T
p.Thr58Ile  ·  KRAS
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Classification rationale
1

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.

PMID:18509354 ↗ clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

PMID:16474405 ↗ PMID:20949621 ↗
4

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).

cspec ↗ spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This 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).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.921. BayesDel score = 0.42458.
SpliceAI ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueT58
Hotspots ↗