About KRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KRAS c.15A>T, p.(Lys5Asn)
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
Approved KRAS functional studies in the RASopathy VCEP materials list p.(Lys5Asn) among pathogenic variants showing abnormal results in two different approved assays, MEK activation and ERK activation, and the cited KRAS functional literature describes aberrant biochemical properties of germline KRAS variants consistent with a gain-of-function effect. This supports PS3 at the Moderate level under the KRAS RASopathy specification.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. Under the KRAS RASopathy specification, absence from controls supports PM2 at the Supporting level.
PP3Supporting
PP3 · supporting
For this missense variant, REVEL is 0.764, which is above the KRAS RASopathy PP3 threshold of at least 0.7. SpliceAI predicts no significant splice effect with a maximum delta score of 0.19, supporting interpretation as a missense rather than splicing mechanism, and BayesDel is also available at 0.0213364. These data support PP3 at the Supporting level.
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, PM2 supporting, 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
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 lies 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.15A>T (p.(Lys5Asn), p.(K5N)) variant has been observed in somatic cancers in COSMIC (COSV56100680, 2 occurrences) and has been reported in ClinVar, including a Pathogenic expert-panel classification from the ClinGen RASopathy Variant Curation Expert Panel.
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population databases.
In approved functional studies used by the RASopathy VCEP, p.(Lys5Asn) showed abnormal results in both MEK activation and ERK activation assays, and published KRAS functional work described aberrant biochemical properties of germline KRAS variants consistent with a gain-of-function effect.
Computational evidence supports a deleterious missense effect because REVEL is 0.764, which is above the KRAS RASopathy PP3 threshold of 0.7, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.19; BayesDel is 0.0213364.
No criteria match.
Met · 4
PS3 ModerateApproved KRAS functional studies in the RASopathy VCEP materials list p.(Lys5Asn) among pathogenic variants showing abnormal results in two different approved assays, MEK activation and ERK activation, and the cited KRAS functional literature describes aberrant biochemical properties of germline KRAS variants consistent with a gain-of-function effect. This supports PS3 at the Moderate level under the KRAS RASopathy specification. Details ▾Hide ▴
Evidence considered
- RASopathy VCEP approved functional study workbook
- MEK activation assay includes K5N among pathogenic KRAS variants
- ERK activation assay includes K5N among pathogenic KRAS variants
- published KRAS functional study reports aberrant biochemical properties for germline KRAS variants
Still missing
- Direct review of the full underlying assay figures would further strengthen the variant-specific functional summary.
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. Under the KRAS RASopathy specification, absence from controls supports PM2 at the Supporting level. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- KRAS RASopathy PM2 requires absence from controls
Sources
PP3 SupportingFor this missense variant, REVEL is 0.764, which is above the KRAS RASopathy PP3 threshold of at least 0.7. SpliceAI predicts no significant splice effect with a maximum delta score of 0.19, supporting interpretation as a missense rather than splicing mechanism, and BayesDel is also available at 0.0213364. These data support PP3 at the Supporting level. Details ▾Hide ▴
Evidence considered
- REVEL 0.764
- SpliceAI max delta 0.19
- BayesDel 0.0213364
- KRAS RASopathy PP3 threshold REVEL >= 0.7
Sources
Not met · 4 · evaluated, threshold not reached
PM1 The KRAS RASopathy specification limits PM1 to the P-loop (amino acids 10-17), Switch I (25-40), Switch II (57-64), and SAK (145-156) domains. p.(Lys5Asn) affects codon 5, which is outside these specified domains, so PM1 is not met. Details ▾Hide ▴
Evidence considered
- PM1 domain boundaries in KRAS RASopathy specification
- codon 5 lies outside the specified PM1 regions
Sources
cspec ↗vcep_alignment_with_pm1_domains_pptx
BA1 This variant is absent from gnomAD v2.1 and v4.1 and therefore does not meet the KRAS RASopathy BA1 threshold of at least 0.05% filtering allele frequency. Details ▾Hide ▴
BS1 This variant is absent from gnomAD v2.1 and v4.1 and therefore does not meet the KRAS RASopathy BS1 threshold of at least 0.025% filtering allele frequency. Details ▾Hide ▴
BP4 For missense variants, the KRAS RASopathy BP4 threshold requires REVEL of 0.3 or lower. This variant has a REVEL score of 0.764, which is above that threshold, so BP4 is not met. SpliceAI shows no significant splice impact with a maximum delta score of 0.19, but that does not override the missense-specific REVEL threshold. Details ▾Hide ▴
Evidence considered
- REVEL 0.764
- BP4 threshold REVEL <= 0.3
- SpliceAI max delta 0.19
Sources
Not assessed · 10 · no assessment recorded
PS1 No retrieved evidence established a different nucleotide change producing the same KRAS p.(Lys5Asn) amino acid substitution as a previously established pathogenic variant, so PS1 was not applied. Details ▾Hide ▴
Evidence considered
- PS1 requires the same amino acid change from a different nucleotide event
- retrieved materials confirmed this exact variant but did not document an alternate nucleotide match
Still missing
- A confirmed pathogenic alternate nucleotide change resulting in p.(Lys5Asn) would be needed.
Sources
PS2 No confirmed de novo occurrence with parental relationship and testing details was identified in the retrieved evidence, so PS2 was not applied. Details ▾Hide ▴
Evidence considered
- PS2 in the KRAS RASopathy framework is point-based for de novo evidence
- no confirmed de novo case details were retrieved
Still missing
- Case-level de novo evidence with parental testing and phenotype details is needed.
Sources
PS4 Although this variant is present in ClinVar and has been observed in somatic cancers, the retrieved evidence did not provide the point-based proband counts or enrichment data required by the KRAS RASopathy specification for PS4. PS4 was therefore not applied. Details ▾Hide ▴
Evidence considered
- KRAS RASopathy PS4 is point-based
- ClinVar shows prior germline submissions including expert panel classification
- retrieved materials did not provide point-qualified case counts
Still missing
- Independent affected proband counts and point assignment under the RASopathy VCEP framework are needed.
Sources
PM5 The retrieved evidence did not document a different established pathogenic missense change at KRAS codon 5 with the case-count detail needed to assign PM5 under the KRAS RASopathy specification, so PM5 was not applied. Details ▾Hide ▴
Evidence considered
- PM5 is codon-based in the KRAS RASopathy specification
- retrieved materials did not establish same-codon pathogenic alternate substitutions
Still missing
- Confirmed pathogenic alternate missense change(s) at codon 5 and the corresponding RASopathy point framework evidence are needed.
Sources
PM6 No presumed or confirmed de novo evidence with sufficient case-level detail was identified in the retrieved materials, so PM6 was not applied. Details ▾Hide ▴
Evidence considered
- PM6 in the KRAS RASopathy framework is point-based for de novo evidence
- no usable PM6-level case detail was retrieved
Still missing
- A reported de novo occurrence without full confirmation
- or with point-qualified evidence
- would be needed.
Sources
PP1 No segregation data were identified showing that this variant tracks with disease across informative meioses, so PP1 was not applied. Details ▾Hide ▴
Evidence considered
- KRAS RASopathy PP1 requires informative meioses
- no segregation evidence retrieved
Still missing
- Family segregation data with informative meioses are needed.
Sources
BS2 No evidence was identified showing this variant in unaffected individuals at the point level required by the KRAS RASopathy specification, so BS2 was not applied. Details ▾Hide ▴
Evidence considered
- BS2 is point-based in the KRAS RASopathy framework
- no unaffected-carrier evidence retrieved
Still missing
- Documented unaffected carriers and the corresponding point assignment are needed.
Sources
BS4 No non-segregation data were identified showing this variant in unaffected relatives or lack of tracking with disease, so BS4 was not applied. Details ▾Hide ▴
Evidence considered
- BS4 requires informative non-segregation evidence
- no such family data were retrieved
Still missing
- A family report demonstrating non-segregation would be needed.
Sources
BP2 No phase information or alternative molecular diagnosis evidence was identified to support BP2, so this criterion was not applied. Details ▾Hide ▴
Evidence considered
- BP2 is point-based in the KRAS RASopathy framework
- no usable phase evidence retrieved
Still missing
- Observed in trans or alternative point-based evidence would be needed under the KRAS RASopathy framework.
Sources
BP5 No alternative molecular explanation or phenotype-based point evidence was identified to support BP5, so this criterion was not applied. Details ▾Hide ▴
Evidence considered
- BP5 is point-based in the KRAS RASopathy framework
- no alternative diagnosis evidence retrieved
Still missing
- An alternate molecular cause or fully explanatory non-RASopathy phenotype with point assignment would be needed.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant and does not fall into the null-variant categories used for PVS1. The variant-specific PVS1 assessment states that it is not a nonsense, frameshift, or canonical ±1/2 splice variant, and the KRAS RASopathy specification marks PVS1 as not applicable for this variant type. Details ▾Hide ▴
Evidence considered
- KRAS RASopathy specification lists PVS1 as not applicable here
- generic PVS1 scaffold does not place this variant in a default PVS1 bucket
Sources
PM3 N/APM3 is not applicable in the KRAS RASopathy specification for this condition framework. Details ▾Hide ▴
PM4 N/AThis is not an in-frame insertion/deletion or protein length-changing variant, so PM4 is not applicable. Details ▾Hide ▴
PP2 N/APP2 is not applicable in the KRAS RASopathy specification. Details ▾Hide ▴
PP4 N/APP4 is not applicable in the KRAS RASopathy specification for this framework. Details ▾Hide ▴
BS3 N/ABS3 is not applicable in the KRAS RASopathy specification. Details ▾Hide ▴
BP1 N/AIn the KRAS RASopathy specification, BP1 is reserved for truncating or canonical splice variants in genes without an established loss-of-function disease mechanism. This variant is missense, so BP1 is not applicable. Details ▾Hide ▴
Evidence considered
- BP1 framework applies to truncating/null variant classes
- current variant is missense
Sources
BP3 N/ABP3 is not applicable in the KRAS RASopathy specification because no known benign repetitive regions are defined for this use. Details ▾Hide ▴
BP6 N/ABP6 is not applicable in the KRAS RASopathy specification. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous, intronic, or non-coding variants with no predicted splice impact. This is a missense variant, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- variant is missense
- BP7 is defined for synonymous/intronic/non-coding variants
Sources
Identifiers
- Gene
- KRAS
- Transcript
- NM_001369786.1
- Coding (HGVS c.)
- NM_001369786.1:c.15A>T
- Protein (HGVS p.)
- NP_001356715.1:p.(Lys5Asn)
- GRCh38
- chr12:25245370 T>A
- GRCh37
- chr12:25398304 T>A
Gene diagram
Every interpreted variant in KRAS, mapped onto the exon structure of NM_001369786.1. Select a row to find it on the plot.
KRASNM_001369786.1
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingFor this missense variant, REVEL is 0.764, which is above the KRAS RASopathy PP3 threshold of at least 0.7. SpliceAI predicts no significant splice effect with a maximum delta score of 0.19, supporting interpretation as a missense rather than splicing mechanism, and BayesDel is also available at 0.0213364. These data support PP3 at the Supporting level. Details ▾Hide ▴
Evidence considered
- REVEL 0.764
- SpliceAI max delta 0.19
- BayesDel 0.0213364
- KRAS RASopathy PP3 threshold REVEL >= 0.7
Sources
BP4 For missense variants, the KRAS RASopathy BP4 threshold requires REVEL of 0.3 or lower. This variant has a REVEL score of 0.764, which is above that threshold, so BP4 is not met. SpliceAI shows no significant splice impact with a maximum delta score of 0.19, but that does not override the missense-specific REVEL threshold. Details ▾Hide ▴
Evidence considered
- REVEL 0.764
- BP4 threshold REVEL <= 0.3
- SpliceAI max delta 0.19
Sources
BP7 N/ABP7 applies to synonymous, intronic, or non-coding variants with no predicted splice impact. This is a missense variant, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- variant is missense
- BP7 is defined for synonymous/intronic/non-coding variants
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.19). REVEL score = 0.764. BayesDel score = 0.0213364.
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
Captured gnomAD v4.1 source record
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/12594/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-25398304-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-25245370-T-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001369786.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/KRAS/K5N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=108104009
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory) 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 = 0.19). REVEL score = 0.764. BayesDel score = 0.0213364.
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 lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56100680, n = 2 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.