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KITc.1725_1739dupLikely pathogenic
Print report
Variant interpretation report

KIT c.1725_1739dup, p.(Gln575_Asp579dup)

NM_000222.2:c.1725_1739dup NP_000213.1:p.(Gln575_Asp579dup) View identifiers
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.

About KIT

No gene-level summary was recorded for this case.

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

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.

PM2Moderate
PM2 · moderate

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%).

PM4Moderate
PM4 · moderate

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.

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.

SpliceAI score
0.030 maximum delta

Recorded SpliceAI maximum delta score: 0.030. 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: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 3 met · 19 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

Met · 3

PM1 ModerateNM_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. Details ▾Hide ▴
Evidence considered
  • 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.
Sources
oncokb ↗
PM2 ModerateThe 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%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (AC=0). Absent from gnomAD v4.1 (AC=0).
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM4 ModerateThis 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. Details ▾Hide ▴
Evidence considered
  • In-frame duplication of 15 bp (NM_000222.2:c.1725_1739dup) in KIT exon 11
  • resulting in 5-amino-acid duplication (p.Q575_D579dup). Not located in a known repetitive region.
Sources
pvs1_variant_assessment

Not met · 19 · evaluated, threshold not reached

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). 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. Details ▾Hide ▴
Evidence considered
  • In-frame duplication of 15 bp in KIT exon 11
  • does not fall into PVS1 null-variant buckets.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PS2 No de novo observation (maternity and paternity confirmed) has been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo data available in ClinVar
  • literature
  • or case materials.
Still missing
  • No parental testing data available for this variant.
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB curated label 'Likely Oncogenic / Likely Gain-of-function' with no variant-specific experimental data confirmed in the available full-text literature. PMID:26619011 mentions KIT only generically.
Still missing
  • No variant-specific functional assay (e.g.
  • kinase activity
  • Ba/F3 transformation
  • phospho-KIT western blot) available in the case packet. OncoKB may reference additional literature not retrieved in this case.
Sources
oncokb ↗
PS4 No case-control data comparing variant prevalence in affected individuals versus controls is available. Details ▾Hide ▴
Evidence considered
  • No case-control or cohort data in ClinVar
  • gnomAD
  • or literature.
Still missing
  • No affected vs. control prevalence statistics.
PM6 No de novo observation (maternity and paternity unconfirmed) has been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo report available.
Still missing
  • No de novo testing data.
PP1 No co-segregation data are available for this variant in affected family members. Details ▾Hide ▴
Evidence considered
  • No segregation or family studies identified.
Still missing
  • No family co-segregation data.
PP3 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.03 (no splice impact). REVEL and BayesDel not applicable (non-SNV).
Still missing
  • No in silico protein-level predictors available for in-frame indels.
Sources
spliceai ↗
PP4 No patient phenotype or family history data are available to assess whether the clinical presentation is highly specific for a KIT-related disorder. Details ▾Hide ▴
Evidence considered
  • No proband phenotype or clinical history provided.
Still missing
  • Proband clinical data not available.
PP5 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. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar. OncoKB somatic label does not qualify as a germline reputable source under ACMG/AMP.
Still missing
  • No germline ClinVar submission or expert panel classification.
Sources
clinvar ↗
BA1 The variant is absent from gnomAD v2.1 and v4.1 (allele frequency = 0, well below the BA1 threshold of >1%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1
  • AF = 0.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from gnomAD v2.1 and v4.1 (allele frequency = 0, well below the BS1 threshold of >0.3%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1
  • AF = 0.
Sources
gnomad_v2 ↗gnomad_v4 ↗
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. Details ▾Hide ▴
Evidence considered
  • No healthy adult carrier data available.
Still missing
  • No population-level healthy adult observation.
BS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB indicates Likely Gain-of-function (deleterious)
  • not a benign functional effect.
Sources
oncokb ↗
BS4 No segregation data are available to demonstrate lack of co-segregation with disease in affected family members. Details ▾Hide ▴
Evidence considered
  • No family segregation data available.
Still missing
  • No segregation analysis data.
BP2 No evidence of this variant observed in trans with a known pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
  • No trans observation data available.
Still missing
  • No phase-resolved genotype data.
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. BP3 is not applicable when the in-frame indel disrupts a functionally critical domain. Details ▾Hide ▴
Evidence considered
  • In-frame duplication disrupts the functionally characterized juxtamembrane autoinhibitory domain
  • not a non-functional repetitive region.
Sources
oncokb ↗
BP4 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.03 addresses splicing only
  • not protein-level impact of the in-frame duplication.
Still missing
  • No protein-level in silico predictors available for in-frame indels.
Sources
spliceai ↗
BP5 No evidence that this variant is found in a case with an alternate molecular basis for disease that would explain the phenotype. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis data available.
Still missing
  • No proband phenotype or alternate diagnosis data.
BP6 No reputable source (e.g., ClinVar expert panel, clinical testing laboratory) reports this variant as benign or likely benign. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no benign classification from any source.
Sources
clinvar ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 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. Details ▾Hide ▴
Evidence considered
  • Not applicable: variant is an in-frame duplication
  • not a nucleotide substitution.
PM5 N/APM5 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. Details ▾Hide ▴
Evidence considered
  • In-frame duplication cannot be assessed under classic same-residue PM5 semantics.
Sources
pm5_candidates
PP2 N/APP2 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. Details ▾Hide ▴
Evidence considered
  • Variant is an in-frame duplication
  • not a missense substitution.
BP1 N/ABP1 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. Details ▾Hide ▴
Evidence considered
  • Variant is an in-frame duplication
  • not a missense substitution.
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
  • Variant is protein-altering (in-frame duplication of 5 amino acids)
  • not synonymous.
PS5 N/APS5 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. Details ▾Hide ▴
Evidence considered
  • PS5 is not defined in the standard ACMG/AMP 2015 framework.

Identifiers

Gene
KIT
Transcript
NM_000222.2
Coding (HGVS c.)
NM_000222.2:c.1725_1739dup
Protein (HGVS p.)
NP_000213.1:p.(Gln575_Asp579dup)
GRCh38
chr4:54727490 A>ACAACTTCCTTATGAT
GRCh37
chr4:55593656 A>ACAACTTCCTTATGAT

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…
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

SpliceAI acceptor lossat -499 bp
0.020
SpliceAI acceptor gainat -7 bp
0.000
SpliceAI donor lossat +56 bp
0.030
SpliceAI donor gainat +447 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.030

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.03 (no splice impact). REVEL and BayesDel not applicable (non-SNV).
Still missing
  • No in silico protein-level predictors available for in-frame indels.
Sources
spliceai ↗
BP4 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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.03 addresses splicing only
  • not protein-level impact of the in-frame duplication.
Still missing
  • No protein-level in silico predictors available for in-frame indels.
Sources
spliceai ↗
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
  • Variant is protein-altering (in-frame duplication of 5 amino acids)
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.
    Describes a statistical algorithm (HotMAPS) to detect significantly mutated residues across cancer types using mutational recurrence. KIT is mentioned in the introductory sentence as one example of a gene with well-studied tumor-specific mutational hotspots alongside KRAS, NRAS, BRAF, and EGFR. The specific variant NM_000222.2:c.1725_1739dup (p.Q575_D579dup) is not identified anywhere in this paper.
    Does not name this variant
    PMID 26619011 ↗
    Quoted passage
    Among the best-studied therapeutic targets in human cancers are proteins encoded by genes with tumor-specific mutational hotspots, such as KRAS, NRAS, BRAF, KIT, and EGFR.

    Introduction, sentence 1 (gene-level mention only)

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 0.030 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

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 = 0.03).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.