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KITc.1679T>ALikely pathogenic
Print report
Variant interpretation report

KIT c.1679T>A, p.Val560Asp

NM_000222.3:c.1679T>A NP_000213.1:p.(Val560Asp) Missense · exon 11 View identifiers
Classification
Likely pathogenic

Variant description:

The KIT NM_000222.3:c.1679T>A (NP_000213.1:p.(Val560Asp)) missense variant has previously been reported in somatic cancers (COSMIC; COSV55386785, n = 66 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: Variant-specific assays showed phosphorylated KIT and imatinib sensitivity below 100 nmol/L, consistent with altered KIT signaling but incompletely documented validation controls. Based on available guidelines, this variant is considered to be Likely Pathogenic.

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

The proto-oncogene KIT encodes a type 3 transmembrane receptor tyrosine kinase. The receptor is activated through dimerization and autophosphorylation upon binding by its ligand, stem cell factor (SCF) also known as mast cell growth factor (MGF) (PMID: 9438854). KIT activation results in increased intracellular signaling through several pathways including PI3K, MAPK and STAT, ultimately leading to cell proliferation and survival (PMID: 17546049, 11896121, 22089421). For patients with wildtype gastrointestinal stromal tumors (GIST; no KIT or PDGFRA mutations), NCCN recommends testing for germline succinate dehydrogenase (SDH) mutations. About 10-15% of GISTs are wildtype; thus, the absence of a mutation does not exclude the diagnosis of GIST. In patients without KIT mutations, a subset of those with advanced GISTs benefit from imatinib (0-45% of patients) (NCCN Soft Tissue Sarcoma v.2.2017). Activating KIT mutations occur in 80 - 90% of GISTs and are distributed over multiple exons with different frequencies (exons 11 (66.1%), exon 9 (13%), exon 13 (1.2%), and exon 17 (0.6%)) (PMID: 15365079, 17268243, 11719439). There are at least eight small molecule tyrosine kinase inhibitors (TKIs) targeting KIT that have been approved by the US Food and Drug Administration with the efficacy of each TKI strongly depending on the location of the activating KIT mutation (PMID: 2427414, 18955458, 19164557).

NCBI Gene ↗ OncoKB ↗
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 Generic ACMG/AMP 2015 with ClinGen SVI recommendations. 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: 4 Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS1Strong
PS1 · strong

Met, because the exact KIT p.Val560Asp substitution was previously reported in multiple GIST studies, including primary tumor cases and variant-specific functional assays.

PS3Supporting
PS3 · supporting

Met, supporting: variant-specific assays showed phosphorylated KIT and imatinib sensitivity below 100 nmol/L, consistent with altered KIT signaling but incompletely documented validation controls.

PM2Supporting
PM2 · supporting

Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, corresponding to observed allele frequency 0 versus the <=0.0001 threshold.

PP3Moderate
PP3 · moderate

Met at moderate strength: missense REVEL 0.823 meets the generic PP3 moderate threshold of >=0.773.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

Likely Pathogenic: PS1 strong plus PP3 moderate satisfy the generic ACMG/AMP fallback rule, with concordant PS3 and PM2 supporting evidence.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

No screenshot for this evidence
REVEL score
0.823 recorded score

Recorded REVEL score: 0.823. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 →
ClinVar submissions
1 reported laboratory submissions

1 Likely pathogenic. ClinVar API review status: criteria provided, single submitter.

Context only ClinVar ↗
Functional evidence
Statement recorded

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

Applied · PS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
66 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV55386785, n = 66 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.

28 criteria with recorded statuses: 4 met · 7 not met · 12 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The codon/residue evidence supports PS1 at strong strength because the exact KIT p.Val560Asp substitution was previously reported in multiple GIST studies.

PM1 remains unassigned because hotspot/domain evidence is present but the required absence of benign variation across the relevant region is not documented.

PM5 and PP2 remain unassigned because their specific comparator and gene-level benign-missense prerequisites are not established.

BP1 is not met because KIT disease evidence supports recurrent activating missense variation rather than a primarily truncating mechanism.

No segregation, non-segregation, or de novo parental-testing evidence sufficient to assess PS2, PM6, PP1, or BS4 was identified for KIT c.1679T>A (p.V560D).

No VCEP covers KIT in this case; generic ACMG/AMP 2015 rules govern.

PS4 remains not assessed because the PS4-indexed papers lack supplied exact-variant extracts or full text needed to verify case-control counts and calculate OR/RR with a confidence interval.

PP4 remains not assessed because patient-level phenotype and family-history data are absent.

PP5 and BP6 are not triggered because the exact ClinVar record has no expert-panel submission; its only assertion is a non-expert single-submitter Likely pathogenic classification.

BP5 is not met because the exact-variant literature does not document a qualifying alternate molecular basis for disease.

The variant is a missense change, so both criteria were adjudicated through the single applicable REVEL path; SpliceAI was not used to support or oppose either criterion.

REVEL 0.823 meets the supplied PP3 moderate threshold but exceeds the supplied BP4 supporting threshold, yielding PP3 moderate and BP4 not met.

Population evidence supports PM2 at supporting strength because the exact variant is absent from gnomAD v2.1 and v4.1.

Population evidence does not support BA1 or BS1, and the available data do not establish BS2.

Met · 4

PS1 StrongACMG_2015Met, because the exact KIT p.Val560Asp substitution was previously reported in multiple GIST studies, including primary tumor cases and variant-specific functional assays. Details ▾Hide ▴
Reasoning

NM_000222.3:c.1679T>A produces KIT p.Val560Asp (V560D). The identical amino-acid substitution was previously reported in GIST tumor cohorts and functional/therapeutic studies, including primary KIT mutation reports in PMID:16551858 and explicit V560D reports in PMID:16954519, PMID:18955458, and PMID:23840364. ClinVar also records this exact variant as likely pathogenic, with a validated eight-PMID trail, although the ClinVar submission is single-submitter rather than expert-panel reviewed. The prior exact protein change is sufficient for PS1; the evidence concerns the protein-level change rather than a splice effect.

Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
  • PMID:16551858, Table 2 and Figure 4 caption: V560D was a primary KIT exon 11 mutation in GIST cases 25 and 26.
  • PMID:16954519, Table 2 and Results: V560D was reported as a primary KIT exon 11 mutation in multiple patients; isolated KIT V560D was tested experimentally.
  • PMID:18955458, Results and Table 3: KIT exon 11 V560D was directly tested in cell-based kinase assays.
  • PMID:23840364, Results: a KIT exon 11 Val560Asp single-mutant construct was directly tested in COS-1 cells.
  • ClinVar variation 375914: exact NM_000222.3(KIT):c.1679T>A (p.Val560Asp), classified likely pathogenic by one criteria-provided clinical submission.
Sources
PMID:16551858 ↗PMID:16954519 ↗PMID:18955458 ↗PMID:23840364 ↗clinvar ↗
PS3 SupportingACMG_2015Met, supporting: variant-specific assays showed phosphorylated KIT and imatinib sensitivity below 100 nmol/L, consistent with altered KIT signaling but incompletely documented validation controls. Details ▾Hide ▴
Reasoning

PS3 is met at supporting strength. The exact KIT c.1679T>A (p.Val560Asp, V560D) variant was evaluated in multiple in-vitro systems. In engineered KIT assays, isolated V560D showed measurable receptor phosphorylation and drug-response behavior: imatinib inhibited the isolated mutant with an IC50 <100 nmol/L, and sunitinib inhibited ligand-activated V560D with an approximate IC50 <100 nmol/L. A separate COS-1 assay directly tested a KIT single-mutant V560D construct and documented inhibition of mutant KIT phosphorylation by tyrosine-kinase inhibitors. Tumor protein extracts from a cohort including V560D also showed phosphorylated KIT, consistent with constitutive gain-of-function in the juxtamembrane autoinhibitory region. These are biologically relevant, variant-specific functional observations across independent assay contexts, but the available evidence does not fully document assay validation, reproducibility, or all control results needed for a stronger calibration; therefore PS3 is conservatively limited to supporting strength.

Rule
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Evidence considered
  • PMID:16954519, Results section, "Secondary Kinase Mutations Lead to Imatinib Resistance In Vitro" and Fig. 7 legend: isolated KIT V560D was very sensitive to imatinib, with IC50 <100 nmol/L; the paper also reports V560D in patients 5, 19, and 34.
  • PMID:18955458, Results, "In Vitro Measures of Activity With Specific Mutants" and Table 3: ligand-activated KIT exon 11 V560D was tested in transiently transfected CHO-cell autophosphorylation assays and was inhibited by sunitinib, with an approximate IC50 <100 nmol/L.
  • PMID:23840364, Results, "Effects of TKIs on KIT with Single Mutation Expressed in COS-1 Cells": a KIT single-mutant V560D construct was tested in COS-1 cells, and imatinib, sunitinib, and nilotinib inhibited phosphorylation of the mutant protein.
  • PMID:15897563, Discussion paragraph beginning "Our studies highlighted" and Table 2: one tumor carried V560D, and available tumor protein extracts for mutations affecting the juxtamembrane region showed phosphorylated KIT at varying levels.
Still missing
  • The available extracts do not fully document assay validation, replicate-level results, or all wild-type and negative-control results.
  • No standardized quantitative functional calibration specific to KIT V560D was provided for escalation beyond supporting strength.
Sources
PMID:16954519 ↗PMID:18955458 ↗PMID:23840364 ↗PMID:15897563 ↗
PM2 SupportingACMG_2015Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, corresponding to observed allele frequency 0 versus the <=0.0001 threshold. Details ▾Hide ▴
Reasoning

PM2 is met at supporting strength. KIT NM_000222.3:c.1679T>A (p.Val560Asp) is absent from gnomAD v2.1 and gnomAD v4.1; therefore its observed allele frequency is 0 in the available population datasets and is below the supplied PM2 supporting threshold of <=0.0001. The variant is a missense SNV, so the indel calling caveat does not apply.

Rule
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Evidence considered
  • gnomAD v2.1 reports the exact variant as absent.
  • gnomAD v4.1 reports the exact variant as absent.
  • The supplied generic PM2 calibration threshold is <=0.0001, and absence corresponds to observed allele frequency 0 in these datasets.
  • The available evidence also reports the variant as absent from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer subsets; the source registry contains no separate keys for those subset records.
Sources
gnomad_v2 ↗gnomad_v4 ↗
PP3 ModerateACMGMet at moderate strength: missense REVEL 0.823 meets the generic PP3 moderate threshold of >=0.773. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, NM_000222.3:c.1679T>A (p.Val560Asp), so the governing generic rule selects the REVEL path only; SpliceAI is not used for PP3 in this situation. REVEL is 0.823, meeting the supplied generic ClinGen SVI moderate PP3 threshold of >=0.773. The threshold is the ClinGen SVI REVEL calibration of Pejaver et al. 2022 (PMID:36413997). BayesDel is not counted because no generic ACMG-strength calibration is established.

Rule
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
Evidence considered
  • NM_000222.3:c.1679T>A is an exonic missense variant producing p.Val560Asp; therefore PP3 uses REVEL only, not SpliceAI.
  • Local REVEL lookup reports 0.823 for chr4:54727447 T>A (GRCh38), meeting the supplied generic PP3 moderate cutoff of >=0.773.
  • The REVEL cutoff is the ClinGen SVI calibration from Pejaver et al. 2022, PMID:36413997.
  • BayesDel score 0.198658 was not used because the governing instructions establish no generic ACMG-strength calibration for BayesDel.
Sources
revel

Not met · 7 · evaluated, threshold not reached

PP5 ACMG_2015Not met: ClinVar shows one non-expert single-submitter Likely pathogenic assertion, with 0 expert-panel submissions, so PP5 is not triggered. Details ▾Hide ▴
Reasoning

The governing PP5 rule concerns a reputable source reporting the variant as pathogenic when the underlying evidence is unavailable for independent evaluation. The exact ClinVar record is a single-submitter Ambry Genetics Likely pathogenic assertion with review status 'criteria provided, single submitter'; the audit records zero expert-panel submissions. Under the required generic rule, this is not an exact-variant expert-panel classification and does not qualify for PP5.

Rule
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
Evidence considered
  • ClinVar variation 375914 exactly matches NM_000222.3(KIT):c.1679T>A (p.Val560Asp), but the only usable assertion is SCV005033443 from Ambry Genetics, classified Likely pathogenic with review status 'criteria provided, single submitter'.
  • The ClinVar submission audit reports expert_panel_submissions: 0; the assertion is therefore not an exact-variant ClinVar expert-panel classification.
Sources
clinvar ↗
BA1 ACMG_2015Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than having a filtering allele frequency or grpmax FAF of at least 5%. Details ▾Hide ▴
Reasoning

BA1 is not met. KIT NM_000222.3:c.1679T>A (p.Val560Asp) was absent from gnomAD v2.1 and gnomAD v4.1, so no filtering allele frequency or grpmax FAF reaches the generic stand-alone threshold of >=0.05. The variant is a missense SNV, so the indel calling caveat does not apply.

Rule
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Evidence considered
  • gnomAD v2.1 reports the exact variant as absent.
  • gnomAD v4.1 reports the exact variant as absent.
  • Generic calibration threshold supplied for BA1: >=0.05 (ACMG/AMP 2015, PMID:25741868).
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 ACMG_2015Not met: gnomAD v2.1 and v4.1 show no observed allele frequency, far below the generic 1% BS1 default threshold. Details ▾Hide ▴
Reasoning

BS1 is not met. The exact variant is absent from gnomAD v2.1 and v4.1, providing no filtering allele frequency or grpmax FAF above the generic 0.01 default. Because there is no elevated population frequency, a disease-prevalence, penetrance, allelic-heterogeneity, or maximum-credible-frequency calculation is not needed to reject BS1 on this evidence.

Rule
Allele frequency is greater than expected for the disorder.
Evidence considered
  • gnomAD v2.1 reports the exact variant as absent.
  • gnomAD v4.1 reports the exact variant as absent.
  • The generic BS1 default supplied for this case is >=0.01; no grpmax FAF is available because the variant is absent.
  • The gnomAD evidence does not identify a governing non-cancer or exome-only VCEP source, and no elevated ancestry-specific frequency is present to require a maximum-credible-frequency calculation.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP1 ACMG_2015Not met: KIT GIST is repeatedly associated with activating missense mutations, including recurrent juxtamembrane variants, rather than primarily truncating variants. Details ▾Hide ▴
Reasoning

BP1 is not supported because the available KIT disease literature identifies missense gain-of-function as a recurring disease mechanism, particularly in the juxtamembrane region and in GIST. PMID:10485475 describes gain-of-function c-KIT mutations in the juxtamembrane domain, and PMID:15897563 reports recurrent missense mutations affecting residues 556-560. This is inconsistent with a gene for which primarily truncating variants are known to cause disease.

Rule
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Evidence considered
  • PMID:10485475: gain-of-function mutations in the juxtamembrane domain of c-KIT have been found in GISTs.
  • PMID:15897563: KIT mutations in GIST are characterized as gain-of-function, with recurrent missense mutations involving residues 556-560.
  • OncoKB KIT V560D record: KIT is described as recurrently mutated in GIST and the variant-specific biological-effect context is gain-of-function.
Sources
PMID:10485475 ↗PMID:15897563 ↗oncokb ↗
BP4 ACMGNot met: missense REVEL 0.823 exceeds the generic BP4 supporting threshold of <=0.29. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, so BP4 uses the REVEL path only; the SpliceAI result cannot be substituted or double-counted for a missense variant. REVEL is 0.823, which exceeds the supplied BP4 supporting cutoff of <=0.29 and therefore does not support no impact. The applicable result is not indeterminate, so BP4 is not met rather than not_assessed. BayesDel is not counted because no generic ACMG-strength calibration is established.

Rule
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
Evidence considered
  • NM_000222.3:c.1679T>A is an exonic missense variant; therefore BP4 uses REVEL only, and the SpliceAI max delta 0.011 is not evidence for BP4 in this missense situation.
  • Local REVEL lookup reports 0.823, which is above all supplied generic BP4 REVEL cutoffs, including the supporting cutoff of <=0.29.
  • BayesDel score 0.198658 was not used because the governing instructions establish no generic ACMG-strength calibration for BayesDel.
Sources
revel
BP5 ACMG_2015Not met: V560D is reported in GIST tumor contexts with additional KIT mutations, but no qualifying alternate molecular basis explaining disease instead of this variant is documented. Details ▾Hide ▴
Reasoning

The governing BP5 rule requires the variant to be found in a case with an alternate molecular basis for disease. Exact-variant papers report V560D in GIST tumors, sometimes alongside secondary KIT mutations or in treatment-resistance contexts, but they do not document an alternate molecular basis that explains the disease instead of this variant in a qualifying germline case. The available evidence therefore does not meet BP5.

Rule
Variant found in a case with an alternate molecular basis for disease.
Evidence considered
  • PMID:16551858 reports primary V560D in GIST cases 25 and 26; case 26 also had secondary V654A and T670I mutations in subsets of tumor samples, but this is a somatic tumor-treatment context and not a documented alternate molecular basis for a germline disease case.
  • PMID:16954519 reports V560D with acquired secondary V654A, D816H, or D820A mutations in imatinib-resistance contexts; these findings do not establish an alternate molecular basis that explains the disease instead of the queried variant.
  • PMID:18955458 and PMID:23840364 study V560D in engineered assays and double-mutant or resistant GIST-cell contexts, not a qualifying BP5 case with an alternate disease-causing molecular basis.
Sources
PMID:16551858 ↗PMID:16954519 ↗PMID:18955458 ↗PMID:23840364 ↗
BP6 ACMG_2015Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign classification and instead records one non-expert Likely pathogenic assertion. Details ▾Hide ▴
Reasoning

The governing BP6 rule concerns a reputable source reporting the variant as benign when the underlying evidence is unavailable for independent evaluation. The exact ClinVar record has no benign or likely benign assertion and has zero expert-panel submissions; it contains a single-submitter Likely pathogenic assertion instead. BP6 is not triggered.

Rule
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
Evidence considered
  • ClinVar variation 375914 exactly matches NM_000222.3(KIT):c.1679T>A (p.Val560Asp), but the record reports one clinical-laboratory Likely pathogenic submission and no benign submission.
  • The ClinVar submission audit reports expert_panel_submissions: 0, so no exact-variant ClinVar expert-panel Benign or Likely benign classification is available.
Sources
clinvar ↗

Not assessed · 12 · no assessment recorded

PS2 ACMG_2015Not assessed: no documented proband phenotype with confirmed maternity and paternity for KIT c.1679T>A. Details ▾Hide ▴
Reasoning

The available evidence does not document a proband with a disease phenotype carrying KIT c.1679T>A together with confirmed maternity and paternity, nor does it establish absence of a family history. Reports of V560D in tumor cohorts are not de novo parental testing evidence. Therefore PS2 cannot be assessed.

Rule
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
Evidence considered
  • The case evidence documents V560D in tumor studies but provides no proband-level de novo result or parental testing data.
  • PMID:15897563 reports familial segregation for a different KIT variant, 1753del3/D579del, not c.1679T>A (p.V560D).
Still missing
  • Proband disease phenotype and family-history documentation
  • Variant testing results for both biological parents
  • Confirmation of maternity and paternity
PS4 ACMG_2015Not assessed: no verified exact-variant case and control counts or OR/RR with 95% CI are available for comparison against the PS4 threshold >5.0 with CI excluding 1.0. Details ▾Hide ▴
Reasoning

The governing PS4 rule requires a significantly increased prevalence in affected individuals compared with controls, with OR or RR >5.0 and a confidence interval excluding 1.0. The literature packet's PS4 index names PMID:17504295, PMID:25394175, and PMID:29434135, but the bundle contains no paper extraction or full text for these papers that verifies exact KIT c.1679T>A/p.Val560Asp case and control counts. The available exact-variant papers report tumor cohorts or functional studies, not a qualifying case-control comparison, and no OR, RR, or confidence interval can be computed from the supplied evidence. Therefore PS4 cannot be adjudicated without retrieving and checking the indexed papers.

Rule
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
Evidence considered
  • The exact-variant papers PMID:16551858, PMID:16954519, PMID:18955458, PMID:23840364, and PMID:15897563 describe KIT V560D in GIST tumor cohorts or laboratory assays; none supplies a verified affected-versus-unaffected control comparison for this variant.
  • The literature_pass.json criteria index lists PMID:17504295, PMID:25394175, and PMID:29434135 for PS4, but no extract or full text for those indexed papers is available in the supplied packet, so their exact-variant case-control evidence remains unresolved.
  • No numeric PS4 result was available; consequently no OR/RR or confidence-interval inequality was evaluated.
Still missing
  • Retrieve and verify PMID:17504295, PMID:25394175, and PMID:29434135 for exact KIT c.1679T>A/p.Val560Asp case and control counts, or a reported OR/RR and 95% CI.
  • If counts are found, compute the OR and 95% CI and document the explicit comparison to OR >5.0 and CI excluding 1.0.
Sources
PMID:16551858 ↗PMID:16954519 ↗PMID:18955458 ↗PMID:23840364 ↗PMID:15897563 ↗
PM1 ACMG_2015Not assessed: Val560 is a documented KIT juxtamembrane hotspot, but the required absence of benign variation across the relevant region is not established. Details ▾Hide ▴
Reasoning

KIT p.Val560Asp lies in the intracellular juxtamembrane region, which is functionally important: PMID:10224103 describes Val-560 within an autoinhibitory amphipathic alpha-helix, and PMID:15897563 reports that 13 of 15 KIT exon 11 mutations in its series involved residues 556-560. The case evidence also reports that V560 is in a statistically significant Cancer Hotspots hotspot. However, the available evidence does not establish the required absence of benign variation across the relevant hotspot/domain, and no VCEP domain table or gene-specific PM1 specification is available. Therefore PM1 cannot be assigned under the generic rule without a documented benign-variation assessment.

Rule
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
Evidence considered
  • Cancer Hotspots result for KIT V560: the queried variant lies in a statistically significant hotspot; the parsed row is incomplete and requires screenshot-level verification.
  • PMID:10224103: Val-560 is in a putative amphipathic alpha-helix in the KIT intracellular juxtamembrane region involved in inhibiting spontaneous receptor phosphorylation.
  • PMID:15897563: 13 of 15 KIT exon 11 mutations affected residues 556-560, and the authors interpret this region as disrupting hydrophobic interactions in the autoinhibitory juxtamembrane region.
  • gnomAD v2.1 and v4.1: the exact c.1679T>A variant is absent, but these records do not document benign variation across the whole hotspot/domain.
Still missing
  • A documented assessment of benign variation across the KIT Val560 hotspot or relevant juxtamembrane domain is required.
Sources
hotspots ↗PMID:10224103 ↗PMID:15897563 ↗gnomad_v2 ↗gnomad_v4 ↗
PM5 ACMG_2015Not assessed: V560A has functional evidence but no documented pathogenic determination, so no different pathogenic missense comparator at Val560 is established. Details ▾Hide ▴
Reasoning

The evidence includes another missense substitution at the same residue, V560A, which produced increased spontaneous KIT phosphorylation in a functional study (PMID:10224103), but that paper does not establish V560A as pathogenic. The available same-residue literature identifies V560D itself and nearby-residue variants, but does not provide a different missense change at Val560 with a documented pathogenic determination. Therefore the specific PM5 prerequisite is not established.

Rule
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Evidence considered
  • PMID:10224103: Val560A caused greater than 10-fold spontaneous KIT phosphorylation, but the paper does not classify V560A as pathogenic.
  • PMID:16551858 and PMID:15897563: V560D is reported, while PMID:15897563 also discusses V559D/V559G; these are not different pathogenic missense changes at residue 560.
Still missing
  • A different missense variant at KIT Val560 with a documented pathogenic determination is needed.
Sources
PMID:10224103 ↗PMID:16551858 ↗PMID:15897563 ↗
PM6 ACMG_2015Not assessed: no proband-level assumed de novo observation for KIT c.1679T>A is documented. Details ▾Hide ▴
Reasoning

The available evidence does not document an assumed de novo KIT c.1679T>A variant in a proband, and no parental testing or family-history information is provided from which an assumed de novo observation could be established. Tumor reports of V560D do not satisfy PM6. Therefore PM6 cannot be assessed.

Rule
Assumed de novo, but without confirmation of paternity and maternity.
Evidence considered
  • The available V560D publications describe tumor cohorts and functional or treatment studies, not an assumed de novo germline observation.
  • No parental testing result for KIT c.1679T>A is documented.
Still missing
  • Proband-level clinical observation for this variant
  • Parental testing or documented absence of the variant in tested parents
  • Family-history information
PP1 ACMG_2015Not assessed: no multiple affected relatives carrying KIT c.1679T>A are documented; the familial report involved a different KIT variant. Details ▾Hide ▴
Reasoning

No multiple affected family members carrying KIT c.1679T>A are documented. PMID:15897563 describes segregation of a different germline KIT variant, 1753del3/D579del, in a GIST kindred; it does not establish segregation of V560D. The reported V560D tumor cases therefore cannot support PP1 for this variant.

Rule
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Evidence considered
  • Tarn et al., PMID:15897563, describes a GIST kindred in which patient 14 and her mother carried germline KIT 1753del3/D579del; this is not c.1679T>A (p.V560D).
  • Tarn et al., PMID:15897563, reports one V560D tumor mutation in the study series but does not provide familial segregation data for V560D.
Still missing
  • Pedigree with affected relatives
  • Variant testing results in affected and unaffected relatives
  • Phenotype details and number of informative meioses
Sources
PMID:15897563 ↗
PP2 ACMG_2015Not assessed: KIT missense gain-of-function is documented, but no gene-level low benign-missense rate or applicable threshold is provided. Details ▾Hide ▴
Reasoning

The available literature supports that activating KIT missense variants are a common disease mechanism in GIST and describes recurrent juxtamembrane missense changes, including V560D. However, the evidence bundle does not provide a gene-level benign-missense rate or an adequately defined low-benign-missense threshold for KIT. Exact absence of this variant from gnomAD cannot substitute for the required gene-level benign missense assessment. The two required PP2 components therefore cannot both be established.

Rule
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Evidence considered
  • PMID:10485475: gain-of-function mutations in the KIT juxtamembrane domain were found in GISTs.
  • PMID:15897563: KIT GIST mutations are described as gain-of-function, with recurrent missense changes concentrated in residues 556-560.
  • gnomAD v2.1 and v4.1: the queried variant is absent, but this is not a gene-level benign missense rate.
Still missing
  • A gene-level assessment demonstrating KIT has a low rate of benign missense variation is required.
Sources
PMID:10485475 ↗PMID:15897563 ↗gnomad_v2 ↗gnomad_v4 ↗
PP4 ACMG_2015Not assessed: the supplied evidence lacks the patient's phenotype or family history needed to establish a highly specific single-etiology disease presentation. Details ▾Hide ▴
Reasoning

The governing PP4 rule requires a patient's phenotype or family history that is highly specific for a disease with a single genetic etiology. The supplied case evidence identifies KIT c.1679T>A/p.Val560Asp and literature involving GIST, but it does not provide the patient's phenotype, family history, or a documented highly specific single-etiology presentation. PP4 therefore cannot be assessed.

Rule
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Evidence considered
  • The case materials identify KIT p.Val560Asp and discuss GIST literature, but do not provide patient-level phenotype or family-history findings.
  • Exact-variant papers describe tumor cohorts or assays rather than this patient's phenotype and therefore cannot substitute for the required patient-level PP4 evidence.
Still missing
  • Obtain the patient's documented phenotype and family history, including the diagnosed disease and features supporting phenotypic specificity.
  • Assess whether the phenotype is highly specific for a disease with a single genetic etiology.
Sources
PMID:16551858 ↗PMID:16954519 ↗PMID:18955458 ↗PMID:23840364 ↗PMID:15897563 ↗
BS2 ACMG_2015Not assessed: population absence does not establish the healthy-adult carrier or homozygote observation required for BS2. Details ▾Hide ▴
Reasoning

BS2 is not assessed. The available population evidence shows absence from gnomAD v2.1 and v4.1, but it does not document an unaffected healthy adult carrying this variant in the zygosity required for the relevant KIT disease model. No homozygote, heterozygote, or hemizygote healthy-adult observation and no confirmed full-penetrance early-onset inheritance model were supplied.

Rule
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
Evidence considered
  • gnomAD v2.1 reports the exact variant as absent and therefore provides no observed homozygote or heterozygote for this variant.
  • gnomAD v4.1 reports the exact variant as absent and therefore provides no observed homozygote or heterozygote for this variant.
  • No supplied source documents a healthy adult with the variant in the zygosity required for BS2.
Still missing
  • A documented healthy adult carrying the variant in the disease-relevant zygosity is needed.
  • The relevant KIT disease inheritance model and expected age-related penetrance are not established in the supplied evidence.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 ACMG_2015Not assessed: no reviewed assay demonstrates that KIT p.Val560Asp has no damaging effect on protein function or splicing. Details ▾Hide ▴
Reasoning

No well-established functional study in the reviewed evidence demonstrates that KIT p.Val560Asp has no damaging effect on protein function or splicing. The available variant-specific studies evaluate phosphorylation, oncogenic signaling, or tyrosine-kinase inhibitor response and do not provide a validated benign functional result. BS3 is therefore not assessed.

Rule
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
Evidence considered
  • The reviewed variant-specific studies measured KIT phosphorylation, signaling, or inhibitor response; none reported a validated normal-function or normal-splicing result that supports BS3.
Still missing
  • A validated assay showing normal KIT protein function or normal splicing for p.Val560Asp is absent from the reviewed evidence.
Sources
PMID:16954519 ↗PMID:18955458 ↗PMID:23840364 ↗PMID:15897563 ↗
BS4 ACMG_2015Not assessed: no affected relatives tested for KIT c.1679T>A are documented, so non-segregation cannot be determined. Details ▾Hide ▴
Reasoning

No affected family members tested for KIT c.1679T>A are documented, so there is no reliable non-segregation result. The familial data in PMID:15897563 concern a different KIT variant and cannot establish lack of segregation for V560D. Therefore BS4 cannot be assessed.

Rule
Lack of segregation in affected members of a family.
Evidence considered
  • Tarn et al., PMID:15897563, provides family testing for KIT 1753del3/D579del, not for KIT c.1679T>A (p.V560D); this cannot be used as non-segregation evidence for V560D.
  • No affected-family-member testing results for KIT c.1679T>A are available.
Still missing
  • Affected relatives carrying or lacking KIT c.1679T>A
  • Variant testing methodology and results for each affected relative
  • Phenotype confirmation and pedigree context
Sources
PMID:15897563 ↗
BP2 ACMG_2015Not assessed: tumor studies report V560D with secondary KIT variants, but no germline phase or pathogenic-partner evidence establishes BP2. Details ▾Hide ▴
Reasoning

BP2 cannot be assessed from the available evidence. PMID:16551858 reports V560D as a primary tumor mutation with secondary KIT mutations in a subset of tumors, and PMID:16954519 reports V560D with secondary V654A/D816H or D820A in cis and a separate V560D case without a secondary mutation; these are somatic tumor observations, not documented affected-proband germline phase, and the partner variants are not established here as pathogenic variants under the BP2 rule. No parent testing or other germline phasing demonstrates either the required trans observation in a fully penetrant dominant disorder or cis observation with a pathogenic variant.

Rule
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
Evidence considered
  • PMID:16551858, Table 2, cases 25 and 26; Figure 4 caption: V560D is reported as a primary KIT exon 11 mutation, with secondary V654A and T670I mutations in subsets of tumor samples from case 26; the study is tumor-tissue sequencing and does not establish germline phase or pathogenicity of the secondary variants.
  • PMID:16954519, Table 2, patients 5, 19, and 34; Table 4; Results: V560D is reported alongside acquired V654A/D816H or D820A in tumor samples, and without a secondary mutation in another patient; the study does not provide affected-proband germline phase evidence for BP2.
Still missing
  • Documented affected-proband germline testing with a pathogenic allele and validated cis/trans phase is unavailable.
  • The reported secondary KIT tumor variants are not established in the reviewed evidence as pathogenic partners for BP2.
Sources
PMID:16551858 ↗PMID:16954519 ↗
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant. Details ▾Hide ▴
Reasoning

PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000222.3:c.1679T>A in KIT is a missense substitution predicted to produce NP_000213.1:p.(Val560Asp). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for KIT, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.

Rule
deterministic_prefilter: requires_null_variant_class
Evidence considered
  • Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
  • VCEP criterion policy: absent
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
PM3 N/ANot applicable: PM3 is restricted to recessive disorders, and this KIT case provides no recessive-disease context or trans-phase testing. Details ▾Hide ▴
Reasoning

PM3 is not applicable because its governing definition is restricted to recessive disorders, whereas the reviewed KIT case provides no recessive-disease context; no parent or offspring testing establishes the queried variant in trans with a pathogenic allele.

Rule
For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
Evidence considered
  • The case summary identifies KIT and a hereditary cancer-predisposing syndrome but provides no recessive inheritance designation, affected-proband segregation data, or parent/offspring phase testing for NM_000222.3:c.1679T>A (p.Val560Asp).
PM4 N/ANot applicable: PM4 requires a protein-length change, and this is a missense variant. Details ▾Hide ▴
Reasoning

PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000222.3:c.1679T>A in KIT is a missense substitution predicted to produce NP_000213.1:p.(Val560Asp). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for KIT, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.

Rule
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
Evidence considered
  • Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
  • VCEP criterion policy: absent
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
BP3 N/ANot applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant. Details ▾Hide ▴
Reasoning

BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000222.3:c.1679T>A in KIT is a missense substitution predicted to produce NP_000213.1:p.(Val560Asp). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for KIT, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.

Rule
deterministic_prefilter: requires_repeat_region_indel
Evidence considered
  • Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
  • VCEP criterion policy: absent
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
BP7 N/ANot applicable: BP7 requires a synonymous variant, and this is a missense variant. Details ▾Hide ▴
Reasoning

BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000222.3:c.1679T>A in KIT is a missense substitution predicted to produce NP_000213.1:p.(Val560Asp). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for KIT, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.

Rule
deterministic_prefilter: requires_synonymous
Evidence considered
  • Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
  • VCEP criterion policy: absent
Sources
generic_acmg_combination_rules

Identifiers

Gene
KIT
Transcript
NM_000222.3
Coding (HGVS c.)
NM_000222.3:c.1679T>A
Protein (HGVS p.)
NP_000213.1:p.(Val560Asp)
GRCh38
chr4:54727447 T>A
GRCh37
chr4:55593613 T>A
Location and type
Exon 11 · missense
ClinVar
458886, 375914, 13856
COSMIC
COSV55386785

Gene diagram

Every interpreted variant in KIT, mapped onto the exon structure of NM_000222.3. Select a row to find it on the plot.

KITNM_000222.3
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

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -456 bp
0.003
SpliceAI acceptor gainat -60 bp
0.001
SpliceAI donor lossat -5 bp
0.011
SpliceAI donor gainat +99 bp
0.004
Pangolin splice lossmagnitude shown
-0.005
Pangolin splice gain
0.038

Other predictors

REVEL
0.823
BayesDel
0.199

How the predictions were used

PP3 ModerateACMGMet at moderate strength: missense REVEL 0.823 meets the generic PP3 moderate threshold of >=0.773. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, NM_000222.3:c.1679T>A (p.Val560Asp), so the governing generic rule selects the REVEL path only; SpliceAI is not used for PP3 in this situation. REVEL is 0.823, meeting the supplied generic ClinGen SVI moderate PP3 threshold of >=0.773. The threshold is the ClinGen SVI REVEL calibration of Pejaver et al. 2022 (PMID:36413997). BayesDel is not counted because no generic ACMG-strength calibration is established.

Rule
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
Evidence considered
  • NM_000222.3:c.1679T>A is an exonic missense variant producing p.Val560Asp; therefore PP3 uses REVEL only, not SpliceAI.
  • Local REVEL lookup reports 0.823 for chr4:54727447 T>A (GRCh38), meeting the supplied generic PP3 moderate cutoff of >=0.773.
  • The REVEL cutoff is the ClinGen SVI calibration from Pejaver et al. 2022, PMID:36413997.
  • BayesDel score 0.198658 was not used because the governing instructions establish no generic ACMG-strength calibration for BayesDel.
Sources
revel
BP4 ACMGNot met: missense REVEL 0.823 exceeds the generic BP4 supporting threshold of <=0.29. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, so BP4 uses the REVEL path only; the SpliceAI result cannot be substituted or double-counted for a missense variant. REVEL is 0.823, which exceeds the supplied BP4 supporting cutoff of <=0.29 and therefore does not support no impact. The applicable result is not indeterminate, so BP4 is not met rather than not_assessed. BayesDel is not counted because no generic ACMG-strength calibration is established.

Rule
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
Evidence considered
  • NM_000222.3:c.1679T>A is an exonic missense variant; therefore BP4 uses REVEL only, and the SpliceAI max delta 0.011 is not evidence for BP4 in this missense situation.
  • Local REVEL lookup reports 0.823, which is above all supplied generic BP4 REVEL cutoffs, including the supporting cutoff of <=0.29.
  • BayesDel score 0.198658 was not used because the governing instructions establish no generic ACMG-strength calibration for BayesDel.
Sources
revel
BP7 N/ANot applicable: BP7 requires a synonymous variant, and this is a missense variant. Details ▾Hide ▴
Reasoning

BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000222.3:c.1679T>A in KIT is a missense substitution predicted to produce NP_000213.1:p.(Val560Asp). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for KIT, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.

Rule
deterministic_prefilter: requires_synonymous
Evidence considered
  • Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
  • VCEP criterion policy: absent
Sources
generic_acmg_combination_rules

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.823. BayesDel score = 0.198658.

9 paper records listed. 5 cited in the classification.

Cited in the classification

  • Analysis of KIT mutations in sporadic and familial gastrointestinal stromal tumors: therapeutic implications through protein modeling.
    Tarn C et al. · 2005 May 15
    The paper reports KIT exon 11 V560D and describes recurrent missense mutations in the juxtamembrane region. Four missense mutations affected residue 559 and one affected residue 560; the authors interpret residues 556-560 as a region where mutations disrupt hydrophobic interactions and cause constitutive gain-of-function activation.
    → PS3 · supporting Names this variant
    PMID 15897563 ↗
    Source detail
    Our studies highlighted that the majority of mutations in the juxtamembrane region of KIT encoded by exon 11 typically involve amino acids 556 to 560 (13 of 15, 87%). Within our series of GIST, we uncovered four missense mutations affecting amino acid 559 (V559D or V559G) and one leading to a substitution at residue 560 (V560D).

    Location Discussion, paragraph beginning ‘Our studies highlighted’; Table 2; Results, KIT mutational analysis and prognosis of gastrointestinal stromal tumor

    Context KIT exons 9, 11, 13, and 17 were sequenced in 25 GIST tumors; mutation-positive tumors were further analyzed by subcloning, protein immunoblotting for total and phosphorylated KIT, and structural modeling.

  • Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate.
    The exact protein substitution V560D is explicitly reported as a primary KIT exon 11 mutation in cases 25 and 26. In case 25, V560D was present without a secondary KIT mutation; in case 26, V560D was the primary mutation and was accompanied by secondary KIT mutations V654A and T670I in subsets of tumor samples.
    → PS1 · strong Names this variant
    PMID 16551858 ↗
    Source detail
    Primary KIT point mutation in exon11 led to the substitution of valine-560 by aspartate (A). Secondary KIT point mutations in exon13 (B) and exon14 (C) resulted in the exchange of valine-654 to alanine and of threonine-670 to isoleucine.

    Location Table 2, cases 25 and 26; Figure 4 caption, case 26; Results, ‘Primary KIT mutations’ and ‘Secondary mutations in KIT under imatinib treatment’

    Context Tumor-tissue sequencing study of 32 patients with advanced GIST under imatinib treatment; 104 tumor samples were analyzed, including microdissected primary tumors, metastases, and treated lesions.

  • Molecular correlates of imatinib resistance in gastrointestinal stromal tumors.
    The paper explicitly reports KIT V560D. V560D was the primary KIT exon 11 mutation in multiple patients, and isolated KIT V560D was very sensitive to imatinib in an engineered assay with an IC50 below 100 nmol/L.
    → PS1 · strong → PS3 · supporting Names this variant
    PMID 16954519 ↗
    Source detail
    The isolated KIT V560D mutation was very sensitive to imatinib (IC50 <100 nmol/L; Fig 4).

    Location Table 2, patients 5, 19, and 34; Results, ‘Secondary Kinase Mutations Lead to Imatinib Resistance In Vitro’; Fig. 7 legend

    Context 147-patient phase II imatinib-treated advanced GIST study; tumor mutation analysis and engineered KIT cDNA biochemical imatinib-sensitivity assays; GIST48 contained homozygous V560D with heterozygous D820A.

  • Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor.
    The paper explicitly studied KIT exon 11 V560D. In cell-based assays, sunitinib inhibited ligand-activated KIT V560D with an approximate IC50 below 100 nmol/L, while double-mutant contexts with activation-loop variants could be resistant.
    → PS1 · strong → PS3 · supporting Names this variant
    PMID 18955458 ↗
    Source detail
    Sunitinib potently inhibited the activity of ligand-activated wild-type KIT, and the KIT exon 11 V560D and exon 9 AY insertion mutants

    Location Results, ‘In Vitro Measures of Activity With Specific Mutants’; Table 3

    Context In vitro KIT autophosphorylation assays using transiently expressed constructs in Chinese hamster ovary cells, supplemented by analysis of imatinib-resistant GIST cell lines including GIST48.

  • Selecting tyrosine kinase inhibitors for gastrointestinal stromal tumor with secondary KIT activation-loop domain mutations.
    The paper explicitly studied KIT exon 11 Val560Asp. In COS-1 cells expressing KIT single mutants, imatinib, sunitinib, and nilotinib inhibited phosphorylation of the KIT Val560Asp mutant; GIST48 additionally carried a D820A secondary mutation.
    → PS1 · strong → PS3 · supporting Names this variant
    PMID 23840364 ↗
    Source detail
    IM, SU, and nilotinib could inhibit the phosphorylation of mutant KIT proteins with single exon 9Ala502_Tyr503insAlaTyr, exon 11Val555_Leu576del, and exon 11Val560Asp mutation in COS-1 cells (Fig. 2a-d).

    Location Results, ‘Effects of TKIs on KIT with Single Mutation Expressed in COS-1 Cells’; Materials and Methods, ‘Cell Lines and Reagents’

    Context In vitro transient-expression assay in COS-1 cells transfected with KIT single-mutant constructs and treated with imatinib, sunitinib, or nilotinib; KIT phosphorylation was assessed by immunoblotting or Luminex assay.

Other recorded publications

  • Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin.
    No paper-specific finding is recorded.
    PMID 23775962 ↗
  • Inhibition of spontaneous receptor phosphorylation by residues in a putative alpha-helix in the KIT intracellular juxtamembrane region.
    Ma Y et al. · 1999
    The paper does not mention KIT c.1679T>A or p.(V560D). It evaluated Val560A in the intracellular juxtamembrane region; in COS-cell assays without SCF stimulation, Val560A caused substantially increased spontaneous KIT tyrosine phosphorylation, reported as greater than 10-fold relative to wild-type KIT. The authors interpreted Val560 as part of a putative amphipathic alpha-helix whose residues help inhibit spontaneous activation of ligand-unoccupied KIT.
    Does not name this variant
    PMID 10224103 ↗
    Quoted passage
    Substantially increased phosphorylation (>10-fold) resulted from removing the side chain of Tyr-553, Trp-557, Val-559, or Val-560

    Results, ‘A Number of Juxtamembrane Residues Are Necessary for Inhibition of Spontaneous KIT Phosphorylation’; Fig. 1

  • Effect of c-kit mutation on prognosis of gastrointestinal stromal tumors.
    Taniguchi M et al. · 1999
    The paper states that gain-of-function mutations in the juxtamembrane domain of c-KIT occur in GIST and evaluates KIT mutations in 124 cases, supporting missense gain-of-function as a disease mechanism rather than a primarily truncating mechanism.
    Does not name this variant
    PMID 10485475 ↗
    Quoted passage
    Gain-of-function mutations in the juxtamembrane domain of the c-kit gene have been found in several GISTs.

    Abstract

  • The UK NEQAS for Molecular Genetics scheme for gastrointestinal stromal tumour: findings and recommendations following four rounds of circulation.
    Wong NA et al. · 2012
    No paper-specific finding is recorded.
    PMID 22685257 ↗

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 0.011 Open source ↗
ClinVar 1 Likely pathogenic 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

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory). (ClinVarID = 375914)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.823. BayesDel score = 0.198658.

Functional

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

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55386785, n = 66 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.