Analysis in progress
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This report is still being assembled — sections appear as each stage finishes. It isn't final yet.
KIT
Final classification
Likely Pathogenic
KIT c.1725_1739dup · p.Gln575_Asp579dup
KIT

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).

Gene
KIT
Transcript
NM_000222.2
HGVS · transcript:coding
NM_000222.2:c.1725_1739dup
Consequence
N/A
GRCh38
chr4:54727490 A>ACAACTTCCTTATGAT
GRCh37
chr4:55593656 A>ACAACTTCCTTATGAT
Basis 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. ▾
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.1725_1739dup

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).1 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.2

PM1 + PM2 + PM4 → Likely Pathogenic
1 oncokb ↗gnomad_v2 ↗gnomad_v4 ↗pvs1_variant_assessment
2 generic_acmg_combination_rules
Gene diagram · NM_000222.2 · variants mapped to exon structure
KIT NM_000222.2
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 19 assessed
Applied · 3
Strength Supporting Moderate Strong Very strong
✓
PM1 moderate Pathogenic
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.
In-frame duplication in the KIT juxtamembrane autoinhibitory domain (exon 11)annotated by OncoKB as Likely Oncogenic / Likely Gain-of-function. Well-established critical functional domain where in-frame indels are known pathogenic drivers.
oncokb ↗
✓
PM2 moderate Pathogenic
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%).
Absent from gnomAD v2.1 (AC=0). Absent from gnomAD v4.1 (AC=0).
gnomad_v2 ↗gnomad_v4 ↗
✓
PM4 moderate Pathogenic
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.
In-frame duplication of 15 bp (NM_000222.2:c.1725_1739dup) in KIT exon 11resulting in 5-amino-acid duplication (p.Q575_D579dup). Not located in a known repetitive region.
Assessed · not applied
Pathogenic
PVS1 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).
PS2 No de novo observation (maternity and paternity confirmed) has been reported for this variant.
PS3 No direct experimental functional data exists for this exact variant in the case packet.
PS4 No case-control data comparing variant prevalence in affected individuals versus controls is available.
PM6 No de novo observation (maternity and paternity unconfirmed) has been reported for this variant.
PP1 No co-segregation data are available for this variant in affected family members.
PP3 Multiple lines of computational evidence do not support a deleterious effect.
PP4 No patient phenotype or family history data are available to assess whether the clinical presentation is highly specific for a KIT-related disorder.
PP5 The variant is absent from ClinVar.
Benign
BA1 The variant is absent from gnomAD v2.1 and v4.1 (allele frequency = 0, well below the BA1 threshold of >1%).
BS1 The variant is absent from gnomAD v2.1 and v4.1 (allele frequency = 0, well below the BS1 threshold of >0.3%).
BS2 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 No well-established functional studies demonstrate no deleterious effect.
BS4 No segregation data are available to demonstrate lack of co-segregation with disease in affected family members.
BP2 No evidence of this variant observed in trans with a known pathogenic variant for a fully penetrant dominant disorder.
BP3 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.
BP4 Multiple lines of computational evidence do not clearly suggest no impact on gene product.
BP5 No evidence that this variant is found in a case with an alternate molecular basis for disease that would explain the phenotype.
BP6 No reputable source (e.g., ClinVar expert panel, clinical testing laboratory) reports this variant as benign or likely benign.
N/A · 5 PS1 · PM5 · PP2 · BP1 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
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
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
SpliceAI ↗
Functional / OncoKB screenshot
Functional Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 1 PMID not cited in assessment
26619011 ↗ Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. ONCOKB