NM_000222.2:c.1652_1663del

KIT · NP_000213.1:p.(Pro551_Val555delinsLeu) · NM_000222.2

GRCh37: chr4:55593585 CCCATGTATGAAG>C · GRCh38: chr4:54727419 CCCATGTATGAAG>C

Gene: KIT Transcript: NM_000222.2

Final call

Likely Pathogenic

PM1 moderate PM2 moderate PM4 moderate

Variant details

Gene

KIT

Transcript

NM_000222.2

Protein

NP_000213.1:p.(Pro551_Val555delinsLeu)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	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.	pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework PMID:9438854
PS1	N/A	PS1 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.
PS2	Not met	No de novo data are available for this variant.
PS3	Not met	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.	PMID:9438854
PS4	Not met	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.
PS5	N/A	PS5 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.
PM1	Met	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.	PMID:9438854 oncokb
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Skipped per case instructions; PM3 is not assessed for this variant.
PM4	Met	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.	PMID:9438854
PM5	N/A	PM5 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.	pm5_candidates
PM6	Not met	No de novo report for this variant was identified in any source.
PP1	Not met	No segregation data are available for this variant.
PP2	N/A	PP2 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.
PP3	Not met	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.	spliceai
PP4	Not met	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	Not met	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.	clinvar
BA1	Not met	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%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	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.
BS3	Not met	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.	PMID:9438854
BS4	Not met	No segregation data are available to demonstrate that this variant does not co-segregate with disease in affected families.
BP1	N/A	BP1 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.
BP2	N/A	BP2 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.
BP3	Not met	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.
BP4	Not met	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.	spliceai
BP5	N/A	BP5 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.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 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.

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