NM_000222.2:c.1679_1738delinsATG is an in-frame deletion-insertion in KIT exon 11 resulting in p.Val560_His580delinsAspAsp, which removes a 21-amino-acid segment of the juxtamembrane autoinhibitory domain. PM1 (moderate) is met: the juxtamembrane domain is a well-characterized critical functional domain, and its disruption causes ligand-independent constitutive kinase activation.1 PM2 (supporting) is met: the variant is absent from gnomAD v2.1 and v4.1 population databases.2 PM4 (supporting) is met: a non-repeat in-frame deletion of 21 amino acids in a functionally critical domain.3 PVS1 is not applicable: this is an in-frame deletion-insertion, not a null variant eligible under ClinGen PVS1 decision tree criteria (PMC6185798).4 PS3 is not met: no variant-specific functional study directly testing p.Val560_His580delinsAspAsp was found in the provided literature. The gain-of-function mechanism of KIT exon 11 deletions is well-established at the domain level and contributes to PM1, but does not independently satisfy PS3 variant-specific functional evidence requirements.5 PS1, PS5, and PM5 are not applicable to this indel variant type. No benign criteria are met. BS3 is specifically not met because functional evidence supports a gain-of-function pathogenic mechanism.6 Total evidence: PM1 (moderate) + PM2 (supporting) + PM4 (supporting). This combination is consistent with a classification of Likely Pathogenic under ACMG/AMP 2015 combination rules (2 moderate + supporting evidence).7
KIT
Final classification
VUS
KIT c.1679_1738delinsATG · p.Val560_His580delinsAspAsp
KIT
NM_000222.2:c.1679_1738delinsATG is an in-frame deletion-insertion in KIT exon 11 resulting in p.Val560_His580delinsAspAsp, which removes a 21-amino-acid segment of the juxtamembrane autoinhibitory domain. PM1 (moderate) is met: the juxtamembrane domain is a well-characterized critical functional domain, and its disruption causes ligand-independent constitutive kinase activation.
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 supporting, PM4 supporting; combination = 1 moderate + 2 supporting, which maps to VUS.
Classification rationale
PM1PM2PM4
VUS
KIT c.1679_1738delinsATG
PM1 + PM2 + PM4
→
VUS
7
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
This variant removes amino acids 560-580 of the KIT juxtamembrane domain (exon 11), a well-characterized critical autoinhibitory domain. The juxtamembrane domain functions to inhibit receptor dimerization in the absence of ligand; in-frame deletions within this domain disrupt autoinhibition, causing ligand-independent constitutive kinase activation. Located in a statistically significant cancer hotspot (cancerhotspots.org).
Cancerhotspots.org identifies this region as a statistically significant hotspot. PMID:15365079 (Corless et al.J Clin Oncol 2004) describes the KIT exon 11 juxtamembrane domain as a critical autoinhibitory regionin-frame deletions disrupt this function
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), indicating it is extremely rare or absent in the general population (allele frequency <0.1% threshold for PM2).
Absent from gnomAD v2.1. Absent from gnomAD v4.1. Absent from gnomAD-Canada v1.0.
✓
PM4
supporting
Pathogenic
This in-frame deletion-insertion removes 21 amino acids (Val560 through His580) and replaces them with 2 amino acids (Asp-Asp), representing a net loss of 19 amino acids in a non-repeat region. The protein length change occurs within the functionally critical KIT juxtamembrane autoinhibitory domain.
In-frame deletion of 21 amino acids in the KIT juxtamembrane domaina non-repeatfunctionally critical region. PMID:15365079 confirms that in-frame deletions in this domain disrupt autoinhibitory function and cause constitutive kinase activation.
Assessed · not applied
Pathogenic
PS2
No de novo observation was identified for NM_000222.2:c.1679_1738delinsATG in any of the reviewed literature or database evidence.
PS3
No variant-specific functional study directly testing NM_000222.2:c.1679_1738delinsATG (p.Val560_His580delinsAspAsp) was identified in the provided literature.
PS4
This variant is absent from ClinVar and no case-control prevalence data in affected individuals versus controls was identified.
PM6
No de novo observation was identified for this variant in any of the reviewed literature.
PP1
No segregation data is available for this variant.
PP2
PP2 applies to genes where missense variants are a common mechanism of disease and the variant is a missense change.
PP3
In silico predictors (REVEL, BayesDel) are not available for this indel variant.
PP4
No specific phenotype data was identified for this variant.
Benign
BA1
This variant is absent from gnomAD v2.1 and v4.1.
BS1
This variant is absent from gnomAD v2.1 and v4.1.
BS2
No evidence of observation in healthy adult individuals was identified for this variant.
BS3
Well-established functional studies show KIT exon 11 in-frame deletions are gain-of-function (activating) mutations that disrupt juxtamembrane autoinhibition and cause constitutive kinase activation.
BS4
No segregation data suggesting lack of segregation with disease was identified.
BP1
BP1 applies to missense variants in genes where truncating variants are the primary mechanism of disease.
BP2
No observation of this variant in trans with a known pathogenic variant was identified.
BP3
BP3 applies to silent and intronic variants without predicted splicing impact.
BP4
While SpliceAI predicts no splicing impact (max delta = 0.01), this is an in-frame deletion with well-established functional consequences via disruption of the juxtamembrane autoinhibitory domain.
BP5
No evidence was identified that this variant is found in a case with an alternative molecular basis for disease.
BP7
BP7 applies to synonymous (silent) variants with no predicted splicing impact.
N/A · 5
PVS1 · PS1 · PM5 · PP5 · BP6
Research & evidence
Population frequency
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 = 0.01).
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.
COSMIC
Cancer hotspots
Somatic evidence
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant lies 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. 4 further PMIDs triaged but not cited — see Sources & References.
Biology of gastrointestinal stromal tumors.
Searched
c.1679_1738delinsATGp.Val560_His580delinsAspAspV560_H580delinsDDV560H580560_580delins
Found
Comprehensive review of GIST biology describing KIT exon 11 juxtamembrane domain as a critical autoinhibitory region. Reports that in-frame deletions within exon 11 disrupt autoinhibition, allowing ligand-independent receptor dimerization and constitutive kinase activation. Notes that deletions tend to affect codons 557-559, and that the wild-type juxtamembrane peptide is inhibitory to activated KIT isoforms. The specific p.Val560_His580delinsAspAsp variant is not individually reported or tested.
Variant
◇ Residue / gene-level — variant not named
Applied to
→PM1 supports · met
→PM4 supports · met
Why
Variant not specifically mentioned but provides authoritative domain-level functional characterization of KIT exon 11 in-frame deletions as gain-of-function. Used to support PM1 (critical domain disruption) and PM4 (in-frame deletion in non-repeat region with functional consequence).
The juxtamembrane region of KIT (exon 11) functions to inhibit receptor dimerization in the absence of SCF. Mutagenesis studies of KIT have demonstrated that small in-frame deletions and insertions or point mutations of this domain disrupt this function, allowing ligand-independent receptor dimerization.
Location Mutations of the Juxtamembrane Domain (exon 11) section, pages 3816-3817 · Context Review article; cites primary mutagenesis studies (Hirota et al 1998, Ma et al 2002, Chan et al 2003) demonstrating constitutive kinase activation of KIT exon 11 in-frame deletion mutants in Ba/F3 transformation assays. · full text
Sources & reference links
Triaged references · 4 PMIDs not cited in assessment
12181401 ↗
Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.
ONCOKB
15451219 ↗
Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial.
ONCOKB
16098458 ↗
Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg.
ONCOKB
17372901 ↗
L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition.
ONCOKB