About KRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KRAS c.451-14T>C, p.?
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: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP6Supporting
BP6 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely benign.
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: BP6 supporting benign; 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
175 / 1,591,272 alleles
gnomAD v4.1: 175 / 1,591,272 alleles. Recorded AF 0.000109975. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98476e-05; MAF= 0.00398%, 11/276052 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000142491; MAF= 0.01425%, 1/7018 alleles, homozygotes = 0); grpmax FAF= 3.979e-05.
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.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
COSMIC ↗
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: 1 met · 4 not met · 10 not assessed · 13 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.451-14T>C (p.?) variant has been reported in ClinVar as Likely Benign, including an expert-panel likely benign assertion from the ClinGen RASopathy Variant Curation Expert Panel.
This variant is present in population databases, including gnomAD v2.1 at 0.00398% (11/276052 alleles) and gnomAD v4.1 at 0.01100% (175/1591272 alleles), which is above the PM2 absence requirement but below the KRAS RASopathy VCEP BS1 threshold of 0.025% and BA1 threshold of 0.05%.
SpliceAI predicts no significant splice impact for this intronic change, with a maximum delta score of 0.01, which does not support PP3 and leaves BP7 incomplete without the additional conservation evidence required by the VCEP rule.
No criteria match.
Met · 1
Not met · 4 · evaluated, threshold not reached
PM2 This variant is present in gnomAD v2.1 at 0.00398% (11/276052 alleles) and in gnomAD v4.1 at 0.01100% (175/1591272 alleles), so it is not absent from controls and PM2_Supporting is not met. Details ▾Hide ▴
Rule
PM2_Supporting requires absence from gnomAD controls.
Evidence considered
- gnomAD v2.1 total AF 3.98476e-05.
- gnomAD v4.1 total AF 0.000109975.
Sources
PP3 SpliceAI predicts no significant splice effect, with a maximum delta score of 0.01, which does not support a splicing impact consistent with disease mechanism; no REVEL score is available because this is not a missense variant. Details ▾Hide ▴
Rule
For splicing impact, the predicted outcome must match disease mechanism; for missense variants, REVEL >=0.7.
Evidence considered
- SpliceAI DS_AG 0.0
- DS_AL 0.0
- DS_DG 0.0
- DS_DL 0.01
- max delta 0.01.
- REVEL not available for this intronic variant.
Sources
BA1 The highest observed filtering allele frequency is below the BA1 threshold of 0.05%: gnomAD v2.1 grpmax FAF is 0.003979% and gnomAD v4.1 grpmax FAF is 0.011553%, so BA1 is not met. Details ▾Hide ▴
Rule
BA1 requires gnomAD filtering allele frequency >=0.05%.
Evidence considered
- gnomAD v2.1 grpmax FAF 3.979e-05 (0.003979%).
- gnomAD v4.1 grpmax FAF 0.00011553 (0.011553%).
Sources
BS1 The highest observed filtering allele frequency is below the BS1 threshold of 0.025%: gnomAD v2.1 grpmax FAF is 0.003979% and gnomAD v4.1 grpmax FAF is 0.011553%, so BS1 is not met. Details ▾Hide ▴
Rule
BS1 requires gnomAD filtering allele frequency >=0.025%.
Evidence considered
- gnomAD v2.1 grpmax FAF 3.979e-05 (0.003979%).
- gnomAD v4.1 grpmax FAF 0.00011553 (0.011553%).
Sources
Not assessed · 10 · no assessment recorded
PS2 No confirmed de novo occurrence with phenotype specificity and parental confirmation was identified for this variant, so PS2 cannot currently be applied. Details ▾Hide ▴
Rule
De novo occurrence scored by the RASopathy VCEP point system.
Evidence considered
- No exact de novo evidence was identified in the reviewed materials.
Still missing
- Case-level parental testing data for this exact variant.
- Phenotype-specific de novo scoring details under the RASopathy VCEP framework.
Sources
PS3 No approved functional assay, RNA study, or other direct experimental evidence demonstrating an abnormal effect of this specific intronic variant was identified, so PS3 is not met. Details ▾Hide ▴
Rule
One approved assay supports PS3_Supporting; two or more different approved assays support PS3_Moderate.
Evidence considered
- RASopathy VCEP functional studies resource was reviewed.
- No exact-variant functional evidence was identified.
Still missing
- Variant-specific RNA or minigene data.
- Approved functional assay evidence for this exact variant.
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4 No affected-case enrichment or point-based case evidence for this exact variant was identified, and the variant is present in gnomAD, so PS4 is not currently supported. Details ▾Hide ▴
Rule
PS4 is point-based in the RASopathy VCEP framework.
Evidence considered
- Variant is present in gnomAD v2.1 and v4.1.
- No case-enrichment evidence for this exact variant was identified.
Still missing
- Variant-specific case counts or enrichment data under the RASopathy VCEP scoring system.
Sources
PM6 No apparently de novo report without full parental confirmation was identified for this exact variant, so PM6 cannot currently be applied. Details ▾Hide ▴
Rule
De novo occurrence without full confirmation scored by the RASopathy VCEP point system.
Evidence considered
- No exact-variant PM6 evidence was identified.
Still missing
- Variant-specific apparent de novo case data.
Sources
PP1 No segregation data for this exact variant were identified, so PP1 is not currently supported. Details ▾Hide ▴
Rule
Supporting at >=3 informative meioses, Moderate at >=5, Strong at >=7.
Evidence considered
- No pedigree or cosegregation evidence was identified.
Still missing
- Family segregation data with informative meioses for this exact variant.
Sources
BS2 No evidence was identified showing this variant in well-phenotyped unaffected individuals sufficient to score BS2 under the RASopathy VCEP point system. Details ▾Hide ▴
Rule
BS2 is point-based in the RASopathy VCEP framework.
Evidence considered
- No BS2-supporting unaffected-carrier dataset was identified.
Still missing
- Unaffected-carrier evidence scored under the VCEP point framework.
Sources
BS4 No non-segregation data for this exact variant were identified, so BS4 is not currently supported. Details ▾Hide ▴
Rule
BS4 requires informative non-segregation; the VCEP notes one informative meiosis can be sufficient.
Evidence considered
- No unaffected-carrier pedigree or non-segregation report was identified.
Still missing
- Family data showing lack of segregation for this exact variant.
Sources
BP2 No evidence was identified for this variant occurring with another pathogenic RASopathy variant in cis or trans in a manner that would score BP2. Details ▾Hide ▴
Rule
BP2 is point-based in the RASopathy VCEP framework.
Evidence considered
- No BP2-relevant phase data were identified.
Still missing
- Phase data with another pathogenic variant and phenotype context.
Sources
BP5 No alternative molecular diagnosis or other point-scoring evidence sufficient for BP5 was identified for this variant. Details ▾Hide ▴
Rule
BP5 is point-based in the RASopathy VCEP framework.
Evidence considered
- No BP5-relevant alternative molecular explanation was identified.
Still missing
- Case-level alternative diagnosis data with phenotype fit under the VCEP point system.
Sources
BP7 This non-canonical intronic variant has SpliceAI scores consistent with no meaningful splice disruption (maximum delta score 0.01), but the reviewed evidence did not establish the nucleotide as not highly conserved and the VCEP notes BP7 should be used in conjunction with BP4 for intronic or non-coding variants, so BP7 is not applied at this time. Details ▾Hide ▴
Rule
Intronic/non-coding variants may use BP7 when splicing algorithms predict no impact and the nucleotide is not highly conserved; VCEP notes use with BP4.
Evidence considered
- SpliceAI max delta score 0.01 indicates no significant predicted splice impact.
- No conservation metric was identified in the reviewed files.
Still missing
- Conservation evidence for the altered nucleotide.
- If required by local practice
- clarified VCEP handling of BP4/BP7 pairing for non-missense intronic variants.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis intronic c.451-14T>C variant is outside the canonical +/-1,2 splice positions and does not fall into the null-variant categories used for PVS1; the KRAS RASopathy VCEP also lists PVS1 as not applicable for this variant type. Details ▾Hide ▴
Rule
Not applicable in the KRAS RASopathy VCEP for this non-canonical intronic variant.
Evidence considered
- KRAS RASopathy VCEP lists PVS1 as not applicable.
- Generic PVS1 scaffold states this variant is not a nonsense
- frameshift
- or canonical splice-site change.
Sources
PS1 N/AThis variant is intronic and has no established protein change, so there is no same-amino-acid substitution evidence to evaluate under PS1. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant.
Evidence considered
- Protein consequence is p.? for an intronic variant.
Sources
PM1 N/AThis variant is intronic and does not alter an amino acid within the KRAS PM1 functional domains, so PM1 is not applicable. Details ▾Hide ▴
Rule
Applicable only to critical and well-established functional protein domains.
Evidence considered
- PM1 applies to specified protein domains only.
- Variant has no defined protein residue change.
Sources
cspec ↗vcep_alignment_with_pm1_domains_pptx
PM3 N/APM3 is not applicable in the KRAS RASopathy VCEP framework for this disorder context. Details ▾Hide ▴
PM4 N/AThis intronic substitution does not cause an in-frame protein length change or stop-loss event, so PM4 is not applicable. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Evidence considered
- Variant is an intronic single-nucleotide substitution.
Sources
PM5 N/AThis variant is intronic and does not create a novel missense change at a codon with other pathogenic substitutions, so PM5 is not applicable. Details ▾Hide ▴
Rule
Novel missense change at an amino acid residue where a different pathogenic missense change has been seen before.
Evidence considered
- Variant has no established codon or amino acid substitution.
Sources
PP2 N/APP2 is not applicable in the KRAS RASopathy VCEP framework. Details ▾Hide ▴
PP4 N/APP4 is not applicable in the KRAS RASopathy VCEP framework. Details ▾Hide ▴
PP5 N/APP5 is not used in this VCEP framework. Details ▾Hide ▴
BS3 N/ABS3 is not applicable in the KRAS RASopathy VCEP framework. Details ▾Hide ▴
BP1 N/ABP1 in this VCEP is intended for truncating or loss-of-function variants in genes where gain-of-function is the main disease mechanism; this non-canonical intronic variant is not a truncating loss-of-function variant. Details ▾Hide ▴
Rule
Use for truncating/LOF variants in genes without established LOF correlation to disease.
Evidence considered
- Variant is intronic and outside canonical splice positions.
Sources
BP3 N/ABP3 is not applicable in the KRAS RASopathy VCEP framework. Details ▾Hide ▴
BP4 N/AThe KRAS RASopathy VCEP BP4 rule is defined for missense variants using REVEL <=0.3, and this intronic variant has no missense consequence or REVEL score. Details ▾Hide ▴
Rule
For missense variants: REVEL <=0.3.
Evidence considered
- Variant is intronic with protein consequence p.?.
- No REVEL score was available
- SpliceAI predicts no significant splice impact.
Sources
Identifiers
- Gene
- KRAS
- Transcript
- NM_001369787.1
- Coding (HGVS c.)
- NM_001369787.1:c.451-14T>C
- Protein (HGVS p.)
- NP_001356716.1:p.?
- GRCh38
- chr12:25209925 A>G
- GRCh37
- chr12:25362859 A>G
Gene diagram
Every interpreted variant in KRAS, mapped onto the exon structure of NM_001369787.1. Select a row to find it on the plot.
KRASNM_001369787.1
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
175 / 1,591,272 alleles
AF 0.00011 · 0 homozygotes · FAF 0.000116
gnomAD v2.1
11 / 276,052 alleles
AF 3.98e-05 · 0 homozygotes · FAF 3.98e-05
By genetic ancestry
gnomAD v4.1
AF 0.00011 · 175 / 1,591,272 alleles · 0 hom · FAF 0.00012
| African/African American10 / 73,838 | 0.00014 |
| European (non-Finnish)155 / 1,163,850 | 0.00013 |
| Remaining individuals8 / 61,612 | 0.00013 |
| Admixed American2 / 58,702 | 3.4e-05 |
0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 4e-05 · 11 / 276,052 alleles · 0 hom · FAF 4e-05
| Remaining individuals1 / 7,018 | 0.00014 |
| African/African American2 / 24,414 | 8.2e-05 |
| European (non-Finnish)8 / 126,988 | 6.3e-05 |
0 alternate alleles recorded in 5 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000109975; MAF= 0.01100%, 175/1591272 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000135432; MAF= 0.01354%, 10/73838 alleles, homozygotes = 0); grpmax FAF= 0.00011553.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98476e-05; MAF= 0.00398%, 11/276052 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000142491; MAF= 0.01425%, 1/7018 alleles, homozygotes = 0); grpmax FAF= 3.979e-05.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI predicts no significant splice effect, with a maximum delta score of 0.01, which does not support a splicing impact consistent with disease mechanism; no REVEL score is available because this is not a missense variant. Details ▾Hide ▴
Rule
For splicing impact, the predicted outcome must match disease mechanism; for missense variants, REVEL >=0.7.
Evidence considered
- SpliceAI DS_AG 0.0
- DS_AL 0.0
- DS_DG 0.0
- DS_DL 0.01
- max delta 0.01.
- REVEL not available for this intronic variant.
Sources
BP7 This non-canonical intronic variant has SpliceAI scores consistent with no meaningful splice disruption (maximum delta score 0.01), but the reviewed evidence did not establish the nucleotide as not highly conserved and the VCEP notes BP7 should be used in conjunction with BP4 for intronic or non-coding variants, so BP7 is not applied at this time. Details ▾Hide ▴
Rule
Intronic/non-coding variants may use BP7 when splicing algorithms predict no impact and the nucleotide is not highly conserved; VCEP notes use with BP4.
Evidence considered
- SpliceAI max delta score 0.01 indicates no significant predicted splice impact.
- No conservation metric was identified in the reviewed files.
Still missing
- Conservation evidence for the altered nucleotide.
- If required by local practice
- clarified VCEP handling of BP4/BP7 pairing for non-missense intronic variants.
Sources
BP4 N/AThe KRAS RASopathy VCEP BP4 rule is defined for missense variants using REVEL <=0.3, and this intronic variant has no missense consequence or REVEL score. Details ▾Hide ▴
Rule
For missense variants: REVEL <=0.3.
Evidence considered
- Variant is intronic with protein consequence p.?.
- No REVEL score was available
- SpliceAI predicts no significant splice impact.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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
175 / 1,591,272 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 ↗
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/138060/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-25362859-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-25209925-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001369787.1%3Ac.4…
- OncoKB ↗www.oncokb.org/gene/KRAS/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=KRAS+c.451-14T%3EC
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= 0.000109975; MAF= 0.01100%, 175/1591272 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000135432; MAF= 0.01354%, 10/73838 alleles, homozygotes = 0); grpmax FAF= 0.00011553.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98476e-05; MAF= 0.00398%, 11/276052 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000142491; MAF= 0.01425%, 1/7018 alleles, homozygotes = 0); grpmax FAF= 3.979e-05.
ClinVar
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratory) and as Likely Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).