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).1 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).2 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).3 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.4 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.5 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.6
KIT
Final classification
Likely Pathogenic
KIT c.1652_1663del · p.Pro551_Val555delinsLeu
KIT
NM_000222.2:c.1652_1663del (p.Pro551_Val555delinsLeu) is an in-frame deletion of 12 bp in exon 11 of KIT.
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.
Classification rationale
PM1PM2PM4
Likely Pathogenic
KIT c.1652_1663del
PM1 + PM2 + PM4
→
Likely Pathogenic
Gene diagram
· NM_000222.2 · variants mapped to exon structure
KIT
NM_000222.2
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
moderate
Pathogenic
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.
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).
✓
PM2
moderate
Pathogenic
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.
Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes).Absent from gnomAD-Canada v1.0 (HostSeq genomes).
✓
PM4
moderate
Pathogenic
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.
In-frame deletion of 5 amino acids (Pro551-Val555) and insertion of 1 leucinecausing net loss of 4 residues in a non-repeat functional domain.Juxtamembrane domain deletions are established to cause constitutive KIT activation (PMID:9438854).
Assessed · not applied
Pathogenic
PVS1
NM_000222.2:c.1652_1663del is an in-frame deletion of 12 bp in exon 11 (juxtamembrane domain), producing p.(Pro551_Val555delinsLeu).
PS2
No de novo data are available 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.
PS4
No case-control or disease-association studies comparing this variant's prevalence in affected versus unaffected individuals are available.
PM6
No de novo report for this variant was identified in any source.
PP1
No segregation data are available for this variant.
PP3
SpliceAI predicts no significant splice impact (max delta score = 0.02).
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.
PP5
This variant is absent from ClinVar.
Benign
BA1
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS2
No data are available to assess whether this variant is observed in healthy adults at a frequency supporting full penetrance exclusion.
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.
BS4
No segregation data are available to demonstrate that this variant does not co-segregate with disease in affected families.
BP3
This in-frame deletion occurs in the KIT juxtamembrane domain, which is not a known repetitive or low-complexity region.
BP4
SpliceAI predicts no splicing impact (max delta = 0.02).
BP6
This variant is absent from ClinVar.
N/A · 8
PS1 · PM3 · PM5 · PP2 · BP1 · BP2 · BP5 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55433582, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.
Searched
c.1652_1663del1652_1663delPro551_Val555delinsLeuP551_V555delinsL12 bp deletion12-bp deletion
Found
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.
Variant
◇ Residue / gene-level — variant not named
Applied to
→PM1 supports · met
→PM4 supports · met
Why
Variant not directly tested, but domain-level evidence confirms that deletions in the KIT juxtamembrane domain cause constitutive gain-of-function activation. Referenced in PM1 and PM4 assessments; insufficient for PS3 because only 5 specific mutations were tested rather than a systematic range characterization.
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 · full text
Sources & reference links