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
KRAS
Final classification
VUS
KRAS c.173C>T · p.Thr58Ile
KRAS
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 ↗
Gene diagram
· NM_004985.4 · variants mapped to exon structure
KRAS
NM_004985.4
Fetching transcript structure from UCSC…
Applied criteria · 4 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
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 supports · met
Germline KRAS mutations cause aberrant biochemical and physical properties leadi
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links