NM_000222.2:c.1725_1739dupACTTCCTTATGATCA

KIT · NP_000213.1:p.(Gln575_Asp579dup) · NM_000222.2

GRCh37: chr4:55593656 A>ACAACTTCCTTATGAT · GRCh38: chr4:54727490 A>ACAACTTCCTTATGAT

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.(Gln575_Asp579dup)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000222.2:c.1725_1739dup (p.Q575_D579dup) is an in-frame duplication of 15 bp in KIT exon 11, located within the juxtamembrane autoinhibitory domain (PM1). The variant is absent from gnomAD v2.1 and v4.1 population databases (PM2). The in-frame duplication occurs in a non-repeat region and alters protein length by 5 amino acids in a functionally critical domain (PM4).

Three moderate pathogenic criteria are met (PM1, PM2, PM4). Under generic ACMG/AMP 2015 combination rules (PMID:25741868), three moderate criteria support a classification of Likely Pathogenic.

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.1725_1739dup is an in-frame duplication (p.Q575_D579dup), not a null variant (nonsense, frameshift, or canonical ±1,2 splice). Under the ClinGen SVI PVS1 decision tree (PMC6185798), in-frame indels do not trigger PVS1 at default strength. The pvs1_variant_assessment confirmed apply_generic_pvs1_framework: false.	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 applies to a different nucleotide change producing the same amino acid change as an established pathogenic missense variant. This is an in-frame duplication, not a single-nucleotide missense substitution.
PS2	Not met	No de novo observation (maternity and paternity confirmed) has been reported for this variant.
PS3	Not met	No direct experimental functional data exists for this exact variant in the case packet. OncoKB annotates the variant as 'Likely Oncogenic' with 'Likely Gain-of-function' but the sole curated paper (PMID:26619011) does not mention this variant. Domain-level inference that exon 11 in-frame duplications are activating in KIT is appropriate for PM1 but does not satisfy PS3's requirement for variant-specific or systematically-characterized-range functional evidence.	oncokb
PS4	Not met	No case-control data comparing variant prevalence in affected individuals versus controls is available.
PS5	N/A	PS5 is not a standard ACMG/AMP criterion under Richards et al. 2015 (PMID:25741868). The standard pathogenic criteria are PVS1, PS1-PS4, PM1-PM6, PP1-PP5.
PM1	Met	NM_000222.2:c.1725_1739dup (p.Q575_D579dup) is an in-frame duplication in KIT exon 11, which encodes the juxtamembrane domain (codons ~545-581). The juxtamembrane domain is a well-characterized autoinhibitory domain; in-frame mutations in this region disrupt autoinhibition and lead to constitutive kinase activation. This is the most common category of KIT driver mutations in gastrointestinal stromal tumors. Although cancerhotspots.org does not flag this specific residue as a statistical hotspot, the domain-level functional characterization satisfies PM1.	oncokb
PM2	Met	The variant is absent from gnomAD v2.1 exomes and gnomAD v4.1 exomes (allele frequency = 0, below the non-VCEP PM2 threshold of <0.1%).	gnomad_v2 gnomad_v4
PM4	Met	This is an in-frame duplication of 15 bp (5 amino acids: p.Q575_D579dup) in a non-repeat region, resulting in increased protein length. The altered protein length in a functionally critical domain supports pathogenicity.	pvs1_variant_assessment
PM5	N/A	PM5 applies to a novel missense change at an amino acid residue where a different pathogenic missense has been observed. NM_000222.2:c.1725_1739dup is an in-frame duplication, not a missense variant. The PM5 candidates module confirmed inapplicable semantics for duplication variants.	pm5_candidates
PM6	Not met	No de novo observation (maternity and paternity unconfirmed) has been reported for this variant.
PP1	Not met	No co-segregation data are available for this variant in affected family members.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common mechanism. NM_000222.2:c.1725_1739dup is an in-frame duplication, not a missense variant.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no significant splice impact (max delta score = 0.03). REVEL and BayesDel scores are unavailable as these tools only evaluate single-nucleotide variants. No HCI prior score is available for KIT.	spliceai
PP4	Not met	No patient phenotype or family history data are available to assess whether the clinical presentation is highly specific for a KIT-related disorder.
PP5	Not met	The variant is absent from ClinVar. OncoKB annotation 'Likely Oncogenic' is derived from somatic cancer curation and does not constitute a reputable germline source for PP5. No expert panel or clinical testing laboratory has reported this variant as pathogenic in a germline context.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1 (allele frequency = 0, well below the BA1 threshold of >1%).	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD v2.1 and v4.1 (allele frequency = 0, well below the BS1 threshold of >0.3%).	gnomad_v2 gnomad_v4
BS2	Not met	No evidence of this variant observed in healthy adults in the homozygous state or in trans with a pathogenic variant for a fully penetrant disorder.
BS3	Not met	No well-established functional studies demonstrate no deleterious effect. OncoKB annotation indicates the opposite direction (Likely Gain-of-function), which is deleterious (activating) rather than benign.	oncokb
BS4	Not met	No segregation data are available to demonstrate lack of co-segregation with disease in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where truncating is the primary known disease mechanism. NM_000222.2:c.1725_1739dup is an in-frame duplication, not a missense variant.
BP2	Not met	No evidence of this variant observed in trans with a known pathogenic variant for a fully penetrant dominant disorder.
BP3	Not met	While this is an in-frame duplication, it occurs within the KIT juxtamembrane domain (exon 11), which is a well-characterized autoinhibitory functional domain, not a repetitive region without known function. BP3 is not applicable when the in-frame indel disrupts a functionally critical domain.	oncokb
BP4	Not met	Multiple lines of computational evidence do not clearly suggest no impact on gene product. SpliceAI predicts no splice impact (max delta = 0.03) but this does not address the protein-level consequence of an in-frame duplication. REVEL and BayesDel cannot evaluate non-SNV variants. Insufficient benign computational evidence to meet BP4.	spliceai
BP5	Not met	No evidence that this variant is found in a case with an alternate molecular basis for disease that would explain the phenotype.
BP6	Not met	No reputable source (e.g., ClinVar expert panel, clinical testing laboratory) reports this variant as benign or likely benign.	clinvar
BP7	N/A	BP7 applies to silent/synonymous variants with no predicted splice impact. NM_000222.2:c.1725_1739dup is an in-frame duplication that alters the protein sequence (p.Q575_D579dup), not a synonymous variant.

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