About KIT
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KIT c.1652_1663del, p.(Pro551_Val555delinsLeu)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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 Not recorded. 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 KIT juxtamembrane domain (aa 550-560) is a well-established critical autoinhibitory domain. Deletions within this domain remove the autoinhibitory function, resulting in constitutive, ligand-independent receptor tyrosine kinase activation as demonstrated in PMID:9438854. The variant deletes residues Pro551 through Val555 (5 amino acids), replacing them with a single leucine, directly disrupting this critical regulatory domain. The functional significance of this domain is further corroborated by the OncoKB designation of Likely Oncogenic with a gain-of-function biological effect.
PM2Moderate
PM2 · moderate
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, indicating it is not present in large population cohorts. The allele frequency is below the 0.1% threshold for PM2 application under generic ACMG/AMP rules.
PM4Moderate
PM4 · moderate
This variant is an in-frame deletion of 12 bp resulting in the net loss of 4 amino acids (Pro551-Val555 deleted, replaced by a single leucine) in the KIT juxtamembrane domain, a non-repeat, functionally critical region. The protein length change directly disrupts the autoinhibitory domain, consistent with a deleterious effect.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate, PM4 moderate; combination = 3 moderate, which maps to Likely Pathogenic.
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
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. 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 identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV55433582, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 3 met · 17 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_000222.2:c.1652_1663del (p.Pro551_Val555delinsLeu) is an in-frame deletion of 12 bp in exon 11 of KIT.
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2).
The deletion removes 5 amino acids (Pro551-Val555) within the KIT juxtamembrane autoinhibitory domain, a well-established critical functional domain where deletions cause constitutive, ligand-independent receptor tyrosine kinase activation (PM1).
The variant causes an in-frame protein length change through deletion of 5 residues and insertion of 1 leucine in a non-repetitive, functionally critical domain (PM4).
Three moderate pathogenic criteria (PM1, PM2, PM4) are met. Per generic ACMG/AMP 2015 combination rules (PMID:25741868), three moderate criteria support a classification of Likely Pathogenic.
The KIT juxtamembrane domain is a gain-of-function hotspot in gastrointestinal stromal tumors; the variant has been observed once in COSMIC (COSV55433582) and is classified as Likely Oncogenic by OncoKB.
PVS1 is not met because this is an in-frame deletion that does not create a null allele, and the established disease mechanism for juxtamembrane domain deletions is gain-of-function rather than loss-of-function.
No criteria match.
Met · 3
PM1 ModerateThe KIT juxtamembrane domain (aa 550-560) is a well-established critical autoinhibitory domain. Deletions within this domain remove the autoinhibitory function, resulting in constitutive, ligand-independent receptor tyrosine kinase activation as demonstrated in PMID:9438854. The variant deletes residues Pro551 through Val555 (5 amino acids), replacing them with a single leucine, directly disrupting this critical regulatory domain. The functional significance of this domain is further corroborated by the OncoKB designation of Likely Oncogenic with a gain-of-function biological effect. Details ▾Hide ▴
Evidence considered
- Variant removes 5 amino acids (Pro551-Val555) from the critical KIT juxtamembrane autoinhibitory domain.
- PMID:9438854 demonstrates that deletions in this domain result in constitutive kinase activation.
- OncoKB classifies this variant as Likely Oncogenic (gain-of-function).
Sources
PM2 ModerateThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, indicating it is not present in large population cohorts. The allele frequency is below the 0.1% threshold for PM2 application under generic ACMG/AMP rules. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes).
- Absent from gnomAD-Canada v1.0 (HostSeq genomes).
Sources
PM4 ModerateThis variant is an in-frame deletion of 12 bp resulting in the net loss of 4 amino acids (Pro551-Val555 deleted, replaced by a single leucine) in the KIT juxtamembrane domain, a non-repeat, functionally critical region. The protein length change directly disrupts the autoinhibitory domain, consistent with a deleterious effect. Details ▾Hide ▴
Evidence considered
- In-frame deletion of 5 amino acids (Pro551-Val555) and insertion of 1 leucine
- causing net loss of 4 residues in a non-repeat functional domain.
- Juxtamembrane domain deletions are established to cause constitutive KIT activation (PMID:9438854).
Sources
Not met · 17 · evaluated, threshold not reached
PVS1 NM_000222.2:c.1652_1663del is an in-frame deletion of 12 bp in exon 11 (juxtamembrane domain), producing p.(Pro551_Val555delinsLeu). It does not create a null variant (nonsense, frameshift, or canonical splice consensus change). The generic PVS1 framework (PMC6185798) does not assign default PVS1 strength to this variant class. Furthermore, KIT juxtamembrane domain deletions are established gain-of-function events that cause constitutive receptor tyrosine kinase activation (PMID:9438854), which is mechanistically incompatible with PVS1, a criterion premised on loss-of-function null alleles. Details ▾Hide ▴
Evidence considered
- In-frame deletion in juxtamembrane domain
- not a null variant.
- KIT juxtamembrane domain deletions confer gain-of-function constitutive activation.
Sources
PS2 No de novo data are available for this variant. Details ▾Hide ▴
Still missing
- No de novo testing has been performed or reported for this variant.
PS3 PMID:9438854 demonstrated that five KIT juxtamembrane domain mutations (all distinct from c.1652_1663del) cause constitutive tyrosine kinase activation in 293T cells and malignant transformation in Ba/F3 cells. The exact variant p.(Pro551_Val555delinsLeu) was not among those tested. The study characterized specific mutations rather than performing a systematic tiling screen or saturation mutagenesis of the domain; domain-level inference from sparse testing falls within PM1 scope, not PS3. No other functional studies testing this exact variant have been identified. Details ▾Hide ▴
Evidence considered
- Juxtamembrane domain deletions tested in PMID:9438854 show constitutive KIT activation
- but the exact 12-bp deletion c.1652_1663del was not among the characterized mutations.
Still missing
- No experimental functional data exists for the exact variant NM_000222.2:c.1652_1663del.
Sources
PS4 No case-control or disease-association studies comparing this variant's prevalence in affected versus unaffected individuals are available. COSMIC records a single somatic occurrence (COSV55433582), but this is not germline case-level evidence suitable for PS4. Details ▾Hide ▴
Evidence considered
- One somatic occurrence in COSMIC
- no germline case-control data.
Still missing
- No germline case-control or cohort study data are available.
PM6 No de novo report for this variant was identified in any source. Details ▾Hide ▴
Still missing
- No de novo testing or reports available.
PP1 No segregation data are available for this variant. Details ▾Hide ▴
Still missing
- No co-segregation data available.
PP3 SpliceAI predicts no significant splice impact (max delta score = 0.02). REVEL and BayesDel scores are not available because this is a deletion variant, not a single nucleotide substitution. Multiple lines of computational evidence do not converge on a deleterious prediction. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.02 (below 0.2 threshold for splice effect).
Still missing
- No in silico missense pathogenicity scores available for this deletion variant.
Sources
PP4 No patient-level phenotype data were provided in the case materials to assess whether the proband's clinical presentation is highly specific for KIT-related disease. Details ▾Hide ▴
Still missing
- No proband phenotype information available to assess PP4.
PP5 This variant is absent from ClinVar. No reputable source has classified this specific variant as pathogenic; therefore there is no expert or consensus-level assertion to credit under PP5. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar (no variation ID
- no classifications
- no submissions).
Sources
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency of 0.0% is far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- Allele frequency 0.0% in all population databases
- below the 1% BA1 threshold.
Sources
BS1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency does not exceed the 0.3% BS1 threshold for standing as a benign polymorphism. Details ▾Hide ▴
Evidence considered
- Allele frequency 0.0% in all population databases
- below the 0.3% BS1 threshold.
Sources
BS2 No data are available to assess whether this variant is observed in healthy adults at a frequency supporting full penetrance exclusion. The variant is absent from all population databases and ClinVar. Details ▾Hide ▴
Still missing
- No observations in healthy adult controls to assess BS2.
BS3 The only functional study retrieved (PMID:9438854) demonstrates that KIT juxtamembrane domain deletions confer constitutive gain-of-function kinase activation, which is a pathogenic mechanism, not a benign one. No well-established in vitro or in vivo functional data suggest a benign or neutral effect for this variant or its domain class. Details ▾Hide ▴
Evidence considered
- PMID:9438854 demonstrates gain-of-function activation (pathogenic)
- not a benign functional effect.
Sources
BS4 No segregation data are available to demonstrate that this variant does not co-segregate with disease in affected families. Details ▾Hide ▴
Still missing
- No segregation or non-segregation data available.
BP3 This in-frame deletion occurs in the KIT juxtamembrane domain, which is not a known repetitive or low-complexity region. The deleted segment (Pro551-Val555) does not consist of repetitive sequence, and the deletion removes a functionally critical autoinhibitory domain. Details ▾Hide ▴
Evidence considered
- Deletion is in a non-repetitive
- functionally critical domain
- not a repetitive region.
BP4 SpliceAI predicts no splicing impact (max delta = 0.02). However, BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. Only one computational predictor (SpliceAI) is available for this deletion variant; REVEL and BayesDel are not applicable. A single benign prediction for a deletion variant that exerts its effect at the protein level (domain disruption) is insufficient to meet BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.02 suggests no splice effect
- but this is a single computational line for a protein-level variant.
Still missing
- Insufficient multi-line computational evidence for BP4
- deletion alters protein sequence directly.
Sources
BP6 This variant is absent from ClinVar. No reputable source has classified this specific variant as benign; therefore there is no expert or consensus-level assertion to credit under BP6. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no benign classifications from any submitter.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to nucleotide substitutions at positions where a different pathogenic change has been established. This variant is a 12-bp in-frame deletion, not a single nucleotide variant. Details ▾Hide ▴
No further detail was recorded.
PM3 N/ASkipped per case instructions; PM3 is not assessed for this variant. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 applies to missense variants at the same amino acid position where a different pathogenic missense change has been established. This variant is an in-frame deletion/insertion (delins), not a missense substitution. The automated PM5 candidate harvesting was unable to establish classic same-residue PM5 semantics for this variant type. Details ▾Hide ▴
Evidence considered
- In-frame deletion variant type is not eligible for classic PM5 which requires missense comparators at the same residue.
Sources
pm5_candidates
PP2 N/APP2 is defined for missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism. This variant is an in-frame deletion, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants where a different pathogenic missense change at the same position has an alternative amino acid substitution. This variant is a 12-bp in-frame deletion, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
BP2 N/ABP2 requires observation of the variant in trans with a known pathogenic variant in a gene associated with a recessive disorder. KIT-associated conditions (e.g., piebaldism, GIST predisposition) follow autosomal dominant inheritance. No in-trans observations are available or expected for this variant. Details ▾Hide ▴
No further detail was recorded.
BP5 N/ABP5 requires an alternative molecular basis for disease in the case that fully explains the phenotype. No alternative molecular diagnosis information is provided in the case materials. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or splicing enhancers. This variant is a 12-bp in-frame deletion/insertion producing a non-synonymous protein change, not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 applies to nucleotide substitutions at positions where a different pathogenic change has been established. This variant is a 12-bp in-frame deletion, not a single nucleotide variant. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- KIT
- Transcript
- NM_000222.2
- Coding (HGVS c.)
- NM_000222.2:c.1652_1663del
- Protein (HGVS p.)
- NP_000213.1:p.(Pro551_Val555delinsLeu)
- GRCh38
- chr4:54727419 CCCATGTATGAAG>C
- GRCh37
- chr4:55593585 CCCATGTATGAAG>C
- COSMIC
- COSV55433582
Gene diagram
Every interpreted variant in KIT, mapped onto the exon structure of NM_000222.2. Select a row to find it on the plot.
KITNM_000222.2
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 KIT
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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
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 SpliceAI predicts no significant splice impact (max delta score = 0.02). REVEL and BayesDel scores are not available because this is a deletion variant, not a single nucleotide substitution. Multiple lines of computational evidence do not converge on a deleterious prediction. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.02 (below 0.2 threshold for splice effect).
Still missing
- No in silico missense pathogenicity scores available for this deletion variant.
Sources
BP4 SpliceAI predicts no splicing impact (max delta = 0.02). However, BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. Only one computational predictor (SpliceAI) is available for this deletion variant; REVEL and BayesDel are not applicable. A single benign prediction for a deletion variant that exerts its effect at the protein level (domain disruption) is insufficient to meet BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.02 suggests no splice effect
- but this is a single computational line for a protein-level variant.
Still missing
- Insufficient multi-line computational evidence for BP4
- deletion alters protein sequence directly.
Sources
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or splicing enhancers. This variant is a 12-bp in-frame deletion/insertion producing a non-synonymous protein change, not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
1 paper record listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
-
PMID 9438854 ↗Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.Hirota et al. (1998) sequenced c-kit cDNA from six GISTs and identified five distinct juxtamembrane domain mutations within an 11-amino acid stretch (Lys550-Val560). All five mutations (a 6-bp deletion, a 15-bp deletion, a 15-bp deletion with a K550I substitution, a V559D point mutation, and a 27-bp deletion) caused constitutive KIT tyrosine phosphorylation in 293T cells and ligand-independent proliferation and tumor formation in Ba/F3 cells. The specific 12-bp deletion c.1652_1663del (p.Pro551_Val555delinsLeu) was not among the mutations identified or functionally characterized in this study.→ PM1 → PM4 Does not name this variant
Source detail
All of the corresponding mutant KIT proteins were constitutively activated without the KIT ligand, stem cell factor (SCF).
Location Figure 3 (mutation alignment); Results paragraphs describing GIST mutations; Figure 4 (constitutive phosphorylation)
Context Transient transfection in 293T HEK cells; stable transfection in Ba/F3 murine lymphoid cells; in vivo tumor formation in nude mice
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 0.020
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 ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000222.2%3Ac.1652_1663del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/4-55593585-CCCATGTATGAAG-C?da…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr4-54727419-CCCATGTATGAAG-C…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/4-54727419-CCCATGTATGAAG-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000222.2%3Ac.1652…
- OncoKB ↗www.oncokb.org/gene/KIT/P551_V555delinsL
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=123263341
- 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 = 0.02).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: 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; COSV55433582, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.