About KRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KRAS c.173C>T, p.(Thr58Ile)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen KRAS VCEP v2.3.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Moderate
PS3 · moderate
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.
PM1Moderate
PM1 · moderate
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.
PP3Supporting
PP3 · supporting
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.
PP5Supporting
PP5 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 1,613,990 alleles
gnomAD v4.1: 1 / 1,613,990 alleles. Recorded AF 6.19583e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
No listed criterion applied
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
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 assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen KRAS VCEP v2.3.0, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 4 not met · 10 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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).
No criteria match.
Met · 4
PS3 ModerateIn 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. Details ▾Hide ▴
Rule
RASopathy VCEP PS3 Moderate: two or more different approved assays.
Evidence considered
- VCEP-approved functional study spreadsheet lists T58I in multiple approved assay classes
- PMID 16474405 reports defective intrinsic GTP hydrolysis
- impaired GAP responsiveness
- and hypersensitive signaling
- PMID 20949621 reports abnormal biochemical and cellular properties for germline KRAS mutants
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studiesPMID:16474405 ↗PMID:20949621 ↗1647440520949621
PM1 ModerateThe 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. Details ▾Hide ▴
Rule
RASopathy VCEP PM1 Moderate for variants in curated critical domains including SW2 (AA 57-64).
Evidence considered
- KRAS Switch II curated domain AA57-AA64
- Thr58 is within the Switch II domain
Sources
cspec ↗vcep_alignment_with_pm1_domains_pptx
PP3 SupportingComputational 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. Details ▾Hide ▴
Rule
RASopathy VCEP PP3 Supporting for missense variants with REVEL ≥0.7.
Evidence considered
- REVEL 0.921
- BayesDel 0.42458
- SpliceAI max delta 0.03
Sources
Not met · 4 · evaluated, threshold not reached
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. Because the RASopathy VCEP PM2 rule requires absence from gnomAD, PM2 is not met. Details ▾Hide ▴
Rule
RASopathy VCEP PM2 Supporting requires absence from gnomAD.
Evidence considered
- Absent from gnomAD v2.1
- Present in gnomAD v4.1 with 1 allele observed
Sources
BA1 The observed population frequency does not reach the BA1 threshold. In gnomAD v4.1 the variant is present at 0.00006% (1/1613990 alleles), which is well below the KRAS RASopathy VCEP BA1 threshold of 0.05%. Details ▾Hide ▴
Rule
RASopathy VCEP BA1 requires gnomAD filtering allele frequency ≥0.05%.
Evidence considered
- gnomAD v4.1 AF 6.19583e-07 (0.00006%)
Sources
BS1 The observed population frequency does not reach the BS1 threshold. In gnomAD v4.1 the variant is present at 0.00006% (1/1613990 alleles), which is below the KRAS RASopathy VCEP BS1 threshold of 0.025%. Details ▾Hide ▴
Rule
RASopathy VCEP BS1 requires gnomAD filtering allele frequency ≥0.025%.
Evidence considered
- gnomAD v4.1 AF 6.19583e-07 (0.00006%)
Sources
BP4 Computational evidence does not support a benign effect. The REVEL score is 0.921, which is above the benign BP4 threshold of 0.3 for this VCEP. Details ▾Hide ▴
Rule
RASopathy VCEP BP4 Supporting for missense variants requires REVEL ≤0.3.
Evidence considered
- REVEL 0.921
Sources
cspec ↗revel
Not assessed · 10 · no assessment recorded
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. Details ▾Hide ▴
Rule
PS1 requires the same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- ClinVar lists the current c.173C>T change
- No alternate nucleotide change producing the same amino acid substitution was documented in the reviewed evidence
Still missing
- Confirmation of whether an alternate nucleotide change producing p.(Thr58Ile) has been established as pathogenic
Sources
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. Details ▾Hide ▴
Rule
RASopathy VCEP de novo criteria use a point-based framework requiring case-level confirmation details.
Evidence considered
- PMID 16474405 reports de novo germline KRAS mutations including T58I
Still missing
- Parental testing confirmation
- Phenotype specificity and point assignment details for the reported proband(s)
Sources
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. Details ▾Hide ▴
Rule
RASopathy VCEP PS4 uses a point-based case-enrichment framework.
Evidence considered
- ClinVar expert panel pathogenic classification
- Multiple disease reports in the literature
Still missing
- Unique proband count
- Evidence that reported cases satisfy the VCEP phenotype scoring framework
- Formal PS4 point total
Sources
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. Details ▾Hide ▴
Rule
RASopathy VCEP PM5 requires a different pathogenic or likely pathogenic residue change at the same codon.
Evidence considered
- No alternate codon 58 pathogenic substitution was documented in the reviewed sources
Still missing
- Confirmation of other pathogenic or likely pathogenic codon 58 substitutions under the RASopathy VCEP framework
Sources
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. Details ▾Hide ▴
Rule
RASopathy VCEP PM6 uses a point-based de novo framework.
Evidence considered
- PMID 16474405 reports de novo KRAS mutations including T58I
Still missing
- Whether the reported occurrence is confirmed or assumed de novo
- Phenotype point assignment for the case(s)
Sources
PP1 No segregation data were identified to show cosegregation of this variant with disease in informative meioses. Details ▾Hide ▴
Rule
RASopathy VCEP PP1 requires informative meioses.
Evidence considered
- No segregation evidence identified
Still missing
- Family segregation data
Sources
BS2 No evidence was identified showing this variant in the number of unaffected individuals required for the RASopathy VCEP BS2 point system. Details ▾Hide ▴
Rule
RASopathy VCEP BS2 uses a point-based framework.
Evidence considered
- No qualifying unaffected carrier data identified
Still missing
- Unaffected adult carrier data with sufficient point assignment
Sources
BS4 No nonsegregation data were identified for this variant. Details ▾Hide ▴
Rule
RASopathy VCEP BS4 requires informative nonsegregation evidence.
Evidence considered
- No nonsegregation evidence identified
Still missing
- Family data showing nonsegregation
Sources
BP2 No phase data or alternative molecular explanation data were identified to support BP2 scoring. Details ▾Hide ▴
Rule
RASopathy VCEP BP2 uses a point-based framework.
Evidence considered
- No qualifying BP2 evidence identified
Still missing
- Phase information with a pathogenic variant or additional point-based evidence
Sources
BP5 No alternative molecular diagnosis or phenotype explanation was identified that would support BP5 scoring. Details ▾Hide ▴
Rule
RASopathy VCEP BP5 uses a point-based framework.
Evidence considered
- No qualifying alternative molecular explanation identified
Still missing
- Documented alternative molecular cause with VCEP point assignment
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the KRAS RASopathy VCEP does not apply PVS1 to this variant type. The generic PVS1 scaffold also indicates that this variant does not fall into a null-variant category. Details ▾Hide ▴
Rule
PVS1 not applicable for this missense variant in the KRAS RASopathy VCEP framework.
Evidence considered
- KRAS RASopathy VCEP lists PVS1 as not applicable
- p.Thr58Ile is a missense change rather than a truncating or canonical splice variant
Sources
PM3 N/APM3 is not applicable in the KRAS RASopathy VCEP framework. Details ▾Hide ▴
Rule
PM3 not applicable for this VCEP.
Evidence considered
- KRAS RASopathy VCEP marks PM3 as not applicable
Sources
PM4 N/AThis variant is a missense substitution and does not create a protein length change such as an in-frame insertion or deletion or stop-loss event, so PM4 is not applicable. Details ▾Hide ▴
Rule
PM4 applies to protein length changes, not missense substitutions.
Evidence considered
- p.Thr58Ile is a missense substitution
Sources
PP2 N/APP2 is not applicable in the KRAS RASopathy VCEP framework. Details ▾Hide ▴
Rule
PP2 not applicable for this VCEP.
Evidence considered
- KRAS RASopathy VCEP marks PP2 as not applicable
Sources
PP4 N/APP4 is not applicable in the KRAS RASopathy VCEP framework. Details ▾Hide ▴
Rule
PP4 not applicable for this VCEP.
Evidence considered
- KRAS RASopathy VCEP marks PP4 as not applicable
Sources
BS3 N/ABS3 is not applicable in the KRAS RASopathy VCEP framework. Details ▾Hide ▴
Rule
BS3 not applicable for this VCEP.
Evidence considered
- KRAS RASopathy VCEP marks BS3 as not applicable
Sources
BP1 N/AThis rule is intended in this framework for truncating variants in a gain-of-function disease setting without established loss-of-function correlation. The current variant is a missense change, so BP1 is not applicable. Details ▾Hide ▴
Rule
KRAS RASopathy VCEP BP1 use is limited to truncating variant contexts described in the specification.
Evidence considered
- p.Thr58Ile is a missense variant
Sources
BP3 N/ABP3 is not applicable in the KRAS RASopathy VCEP framework because no benign repetitive region rule is defined for this gene set. Details ▾Hide ▴
Rule
BP3 not applicable for this VCEP.
Evidence considered
- KRAS RASopathy VCEP marks BP3 as not applicable
Sources
BP6 N/ABP6 is not applicable in the KRAS RASopathy VCEP framework. Details ▾Hide ▴
Rule
BP6 not applicable for this VCEP.
Evidence considered
- KRAS RASopathy VCEP marks BP6 as not applicable
Sources
BP7 N/AThis is a missense variant rather than a synonymous or relevant intronic change, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous or certain noncoding variants with no predicted splice impact.
Evidence considered
- p.Thr58Ile is a missense substitution
Sources
Identifiers
- Gene
- KRAS
- Transcript
- NM_004985.4
- Coding (HGVS c.)
- NM_004985.4:c.173C>T
- Protein (HGVS p.)
- NP_004976.2:p.(Thr58Ile)
- GRCh38
- chr12:25227351 G>A
- GRCh37
- chr12:25380285 G>A
Gene diagram
Every interpreted variant in KRAS, mapped onto the exon structure of NM_004985.4. Select a row to find it on the plot.
KRASNM_004985.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in KRAS
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
1 / 1,613,990 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,990 alleles · 0 hom
| European (Finnish)1 / 64,002 | 1.6e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).
Statements
gnomAD 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).
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingComputational 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. Details ▾Hide ▴
Rule
RASopathy VCEP PP3 Supporting for missense variants with REVEL ≥0.7.
Evidence considered
- REVEL 0.921
- BayesDel 0.42458
- SpliceAI max delta 0.03
Sources
BP4 Computational evidence does not support a benign effect. The REVEL score is 0.921, which is above the benign BP4 threshold of 0.3 for this VCEP. Details ▾Hide ▴
Rule
RASopathy VCEP BP4 Supporting for missense variants requires REVEL ≤0.3.
Evidence considered
- REVEL 0.921
Sources
cspec ↗revel
BP7 N/AThis is a missense variant rather than a synonymous or relevant intronic change, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous or certain noncoding variants with no predicted splice impact.
Evidence considered
- p.Thr58Ile is a missense substitution
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.921. BayesDel score = 0.42458.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,613,990 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243114
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/12588/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-25380285-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-25227351-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004985.4%3Ac.173C…
- OncoKB ↗www.oncokb.org/gene/KRAS/T58I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=107970962
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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).
gnomAD v2.1
Absent from gnomAD v2.1.
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
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55527371, n = 26 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.