About KRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KRAS c.35_37delinsATT, p.(Gly12_Gly13delinsAspCys)
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM1Moderate
PM1 · moderate
The variant alters codons 12 and 13, which lie within the P-loop domain (AA 10-17), a critical and well-established functional domain in KRAS per the RASopathy VCEP. The P-loop is one of four designated PM1 domains (along with SW1, SW2, and SAK). Additionally, the residue is identified as a statistically significant hotspot by cancerhotspots.org.
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the RASopathy VCEP requirement for PM2_Supporting (variant must be absent from controls).
PM4Moderate
PM4 · moderate
NM_033360.3:c.35_37delinsATT is an in-frame deletion-insertion in a non-repeat region resulting in a protein length change (replacement of two residues with two different residues). Per the RASopathy VCEP, PM4 applies at moderate strength because there are no known benign repetitive areas in RASopathy genes (BP3 is not applicable).
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: PM1 moderate, PM2 supporting, PM4 moderate; 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KRAS, a GTPase which functions as an upstream regulator of the MAPK pathway, is frequently mutated in various cancer types including lung, colorectal
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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: 3 met · 16 not met · 0 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_033360.3:c.35_37delinsATT (p.Gly12_Gly13delinsAspCys) is an in-frame deletion-insertion in exon 2 of KRAS, altering codons 12 and 13 within the P-loop domain (AA 10-17), a critical functional domain per the ClinGen RASopathy Expert Panel specifications v2.3.0.
The variant is absent from gnomAD population databases (v2.1, v4.1, and Canada), meeting PM2 at supporting strength per the RASopathy VCEP.
The variant lies within the P-loop domain (AA 10-17), a well-established functional domain, and the residue is a statistically significant hotspot, meeting PM1 at moderate strength.
As an in-frame deletion-insertion in a non-repeat region, the variant meets PM4 at moderate strength per the RASopathy VCEP.
No variant-specific functional studies, de novo observations, segregation data, or proband reports are available. The variant is absent from ClinVar and COSMIC.
The combined evidence (PM1 moderate, PM4 moderate, PM2 supporting) yields 2 moderate and 1 supporting pathogenic criteria, which does not meet any RASopathy VCEP combination rule for Pathogenic or Likely Pathogenic. No benign criteria are met. The variant is classified as a Variant of Uncertain Significance (VUS) under the ClinGen RASopathy Expert Panel specifications for KRAS v2.3.0.
No criteria match.
Met · 3
PM1 ModerateThe variant alters codons 12 and 13, which lie within the P-loop domain (AA 10-17), a critical and well-established functional domain in KRAS per the RASopathy VCEP. The P-loop is one of four designated PM1 domains (along with SW1, SW2, and SAK). Additionally, the residue is identified as a statistically significant hotspot by cancerhotspots.org. Details ▾Hide ▴
Evidence considered
- VCEP defines P-loop (AA 10-17) as a critical functional domain eligible for PM1 at moderate strength. cancerhotspots.org independently confirms the residue is a statistically significant hotspot.
Sources
cspec ↗vcep_alignment_with_pm1_domains_pptx
PM2 SupportingThe variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the RASopathy VCEP requirement for PM2_Supporting (variant must be absent from controls). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes).
- Absent from gnomAD-Canada v1.0 (genomes).
Sources
PM4 ModerateNM_033360.3:c.35_37delinsATT is an in-frame deletion-insertion in a non-repeat region resulting in a protein length change (replacement of two residues with two different residues). Per the RASopathy VCEP, PM4 applies at moderate strength because there are no known benign repetitive areas in RASopathy genes (BP3 is not applicable). Details ▾Hide ▴
Evidence considered
- In-frame delins in a non-repeat region of KRAS.
- BP3 is not applicable per VCEP (no known benign repetitive areas in RASopathy genes).
Sources
Not met · 16 · evaluated, threshold not reached
PS1 This variant produces a complex double amino acid substitution p.(Gly12_Gly13delinsAspCys). Although G12D and G13C are individually established pathogenic changes in KRAS, this variant is a unique in-frame delins that alters two residues simultaneously and does not match any single established pathogenic amino acid change. PS1 is calibrated for a variant producing the same single amino acid change as a known pathogenic variant. Details ▾Hide ▴
Evidence considered
- PS1 requires the same amino acid change as a previously established pathogenic variant. The variant produces a double substitution G12D + G13C which is not a single established pathogenic change.
Sources
PS2 No de novo data are available for this variant. The variant has not been reported in any proband, and no parental testing data exist. Details ▾Hide ▴
Evidence considered
- No de novo observations reported in ClinVar or the literature.
Still missing
- No proband data or parental testing available.
PS3 No variant-specific functional data are available for NM_033360.3:c.35_37delinsATT. The RASopathy VCEP has approved KRAS functional assays (RAS Activation Assay, ERK Activation Assay) that include G12V as a validated pathogenic control, but this exact variant has not been directly tested in any published functional study. Domain-level inference from G12 missense variant data does not satisfy PS3's requirement for variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- VCEP-approved KRAS functional assays exist (RAS Activation
- ERK Activation) but this exact variant has not been tested. G12V is a validated pathogenic control in the approved assays
- but this is not the same variant.
Still missing
- No functional study has directly tested c.35_37delinsATT (p.G12_G13delinsDC).
Sources
vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4 No probands with this variant have been reported. The variant is absent from ClinVar and no case reports exist in the literature. PS4 requires proband counts to meet point-based scoring thresholds (≥1 point for supporting). Details ▾Hide ▴
Evidence considered
- The variant is absent from ClinVar
- no affected individuals have been reported.
Still missing
- No proband data available for prevalence assessment.
Sources
PM6 No assumed or confirmed de novo data are available for this variant. No probands have been reported. Details ▾Hide ▴
Evidence considered
- No de novo observations reported.
Still missing
- No de novo data.
PP1 No co-segregation data are available for this variant. The RASopathy VCEP requires at least 3 informative meioses for supporting-level PP1. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No family studies or segregation data.
PP3 PP3 in the RASopathy VCEP requires REVEL ≥0.7 for missense variants. REVEL and BayesDel scores are not available for this indel variant. SpliceAI predicts no significant splice impact (max delta score 0.01), and splice alteration does not match the gain-of-function disease mechanism. No computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL score not available (indel
- not missense).
- SpliceAI max delta score 0.01 (no predicted splice impact).
Still missing
- No in silico score available for this indel variant type.
Sources
BA1 The RASopathy VCEP BA1 threshold is gnomAD filtering allele frequency ≥0.05%. The variant is absent from all gnomAD datasets (v2.1, v4.1, and Canada). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD
- frequency of 0% does not meet the ≥0.05% BA1 threshold.
Sources
BS1 The RASopathy VCEP BS1 threshold is gnomAD filtering allele frequency ≥0.025%. The variant is absent from all gnomAD datasets (v2.1, v4.1, and Canada). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD
- frequency of 0% does not meet the ≥0.025% BS1 threshold.
Sources
BS2 No data are available regarding observation of this variant in healthy adult individuals. The RASopathy VCEP requires point-based scoring based on phenotypic specifications. Details ▾Hide ▴
Evidence considered
- No healthy adult carrier data available.
Still missing
- No healthy control data with this variant.
BS4 No segregation data are available to assess lack of segregation in affected family members. The RASopathy VCEP requires only one informative meiosis for BS4 at strong level. Details ▾Hide ▴
Evidence considered
- No family segregation or non-segregation data available.
Still missing
- No family studies to demonstrate lack of segregation.
BP1 BP1 in the RASopathy VCEP applies to truncating variants (nonsense, frameshift, canonical splice site, initiation codon, entire gene or multi-exon deletion) in genes where LOF is not the disease mechanism. This variant is an in-frame deletion-insertion, not a truncating variant. Details ▾Hide ▴
Evidence considered
- Variant is an in-frame delins
- not a truncating variant (nonsense
- frameshift
- or canonical splice site).
Sources
BP2 No data are available regarding an alternative molecular cause of a RASopathy in the same gene. The RASopathy VCEP requires point-based scoring for BP2. Details ▾Hide ▴
Evidence considered
- No data on alternative molecular cause in the same gene.
Still missing
- No alternative molecular cause data.
BP4 BP4 in the RASopathy VCEP requires REVEL ≤0.3 for missense variants. REVEL and BayesDel scores are not available for this indel variant. SpliceAI predicts no significant splice impact (max delta 0.01), but the VCEP BP4 rule is calibrated specifically for REVEL thresholds on missense variants, not SpliceAI on indels. Details ▾Hide ▴
Evidence considered
- REVEL score not available (indel).
- SpliceAI max delta 0.01
- no splice impact predicted.
Still missing
- REVEL not available for indel variants.
Sources
BP5 No data are available regarding an alternative molecular cause of a RASopathy in a different gene. The RASopathy VCEP requires point-based scoring for BP5. Details ▾Hide ▴
Evidence considered
- No data on alternative molecular cause in a different gene.
Still missing
- No alternative molecular cause data.
BP7 BP7 applies to synonymous (silent) variants with no predicted splice impact. This variant is an in-frame deletion-insertion that changes two amino acids (Gly12Asp and Gly13Cys), and is therefore not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is not synonymous
- it changes two amino acids: p.(Gly12_Gly13delinsAspCys).
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThe ClinGen RASopathy Expert Panel marks PVS1 as not applicable for KRAS (VCEP v2.3.0). The established disease mechanism for RASopathies is gain-of-function; loss-of-function variants are not a known mechanism, and PVS1 is calibrated for null variants in genes where LOF causes disease. Details ▾Hide ▴
Evidence considered
- PVS1 is explicitly marked Not Applicable in the KRAS RASopathy VCEP criteria v2.3.0.
Sources
PM5 N/APM5 is defined for missense variants at the same codon where a different pathogenic missense has been established. This variant is an in-frame deletion-insertion (delins), not a missense substitution. The PM5 candidates pipeline confirms the variant class is not missense-like. Details ▾Hide ▴
Evidence considered
- Variant class is in-frame delins
- not missense
- PM5 framework is not applicable.
Sources
pm5_candidates
PP2 VCEPPP2 is marked as not applicable by the KRAS RASopathy VCEP because the missense z-score is <3.09 in gnomAD. Details ▾Hide ▴
Evidence considered
- VCEP declares PP2 not applicable: KRAS missense z-score <3.09 in gnomAD.
Sources
PP4 VCEPPP4 is marked as not applicable by the KRAS RASopathy VCEP; see PS4 for patient phenotype data. Details ▾Hide ▴
Evidence considered
- VCEP declares PP4 not applicable
- phenotype specificity is handled via PS4.
Sources
PP5 VCEPPP5 is marked as Not Applicable for this VCEP by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Additionally, the variant is absent from ClinVar and no reputable source has classified it. Details ▾Hide ▴
BS3 VCEPBS3 is marked as not applicable by the KRAS RASopathy VCEP. Details ▾Hide ▴
BP3 VCEPBP3 is marked as not applicable by the KRAS RASopathy VCEP because there are no known benign repetitive areas in RASopathy genes. Details ▾Hide ▴
Evidence considered
- VCEP declares BP3 not applicable: no known benign repetitive areas in RASopathy genes.
Sources
BP6 VCEPBP6 is marked as Not Applicable for this VCEP by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Additionally, the variant is absent from ClinVar and no reputable source has classified it as benign. Details ▾Hide ▴
PS5 N/APS5 is not specified in the KRAS RASopathy VCEP criteria v2.3.0. Same-codon comparisons are handled by PM5 in this framework. Details ▾Hide ▴
Identifiers
- Gene
- KRAS
- Transcript
- NM_033360.3
- Coding (HGVS c.)
- NM_033360.3:c.35_37delinsATT
- Protein (HGVS p.)
- NP_203524.1:p.(Gly12_Gly13delinsAspCys)
- GRCh38
- chr12:25245348 CAC>AAT
- GRCh37
- chr12:25398282 CAC>AAT
Gene diagram
Every interpreted variant in KRAS, mapped onto the exon structure of NM_033360.3. Select a row to find it on the plot.
KRASNM_033360.3
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in KRAS
—
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
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 PP3 in the RASopathy VCEP requires REVEL ≥0.7 for missense variants. REVEL and BayesDel scores are not available for this indel variant. SpliceAI predicts no significant splice impact (max delta score 0.01), and splice alteration does not match the gain-of-function disease mechanism. No computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL score not available (indel
- not missense).
- SpliceAI max delta score 0.01 (no predicted splice impact).
Still missing
- No in silico score available for this indel variant type.
Sources
BP4 BP4 in the RASopathy VCEP requires REVEL ≤0.3 for missense variants. REVEL and BayesDel scores are not available for this indel variant. SpliceAI predicts no significant splice impact (max delta 0.01), but the VCEP BP4 rule is calibrated specifically for REVEL thresholds on missense variants, not SpliceAI on indels. Details ▾Hide ▴
Evidence considered
- REVEL score not available (indel).
- SpliceAI max delta 0.01
- no splice impact predicted.
Still missing
- REVEL not available for indel variants.
Sources
BP7 BP7 applies to synonymous (silent) variants with no predicted splice impact. This variant is an in-frame deletion-insertion that changes two amino acids (Gly12Asp and Gly13Cys), and is therefore not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is not synonymous
- it changes two amino acids: p.(Gly12_Gly13delinsAspCys).
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
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/?term=NM_033360.3%3Ac.35_37delinsATT
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-25398282-CAC-AAT?dataset=g…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-25245348-CAC-AAT?datase…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-25245348-CAC-AAT
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_033360.3%3Ac.35_3…
- OncoKB ↗www.oncokb.org/gene/KRAS/G12_G13delinsDC
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=KRAS+c.35_37delinsATT
- 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KRAS, a GTPase which functions as an upstream regulator of the MAPK pathway, is frequently mutated in various cancer types including lung, colorectal
Somatic
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant lies in a statistically significant hotspot.