About PDGFRA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PDGFRA c.2525A>T, p.(Asp842Val)
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.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
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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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Moderate
PS3 · moderate
PDGFRA D842V has been characterized as a gain-of-function, constitutively activating mutation in multiple independent functional studies across several cell line systems (CHO, 293T, Ba/F3), demonstrating ligand-independent autophosphorylation and transforming activity. Five independent publications confirmed constitutive kinase activation. All functional evidence derives from somatic GIST contexts; no germline-specific functional studies are available, which limits the strength applied.
PM1Moderate
PM1 · moderate
Asp842 is located in the activation loop (exon 18) of the PDGFRA tyrosine kinase domain, a critical functional domain. This residue lies within a statistically significant mutational hotspot and is the most frequently mutated codon in PDGFRA-driven GIST.
PM2Moderate
PM2 · moderate
This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0, meeting the PM2 threshold for absence from population databases (allele frequency <0.1%).
PP3Supporting
PP3 · supporting
REVEL predicts a damaging effect (score 0.861, well above the 0.5 threshold). BayesDel score is 0.343 (intermediate). SpliceAI predicts no splicing impact (max delta 0.02). Multiple in silico lines are mixed, but REVEL strongly supports pathogenicity, providing supporting-level evidence.
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: PS3 moderate, PM1 moderate, PM2 moderate, PP3 supporting; combination = 3 moderate + 1 supporting, 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: no assertion criteria provided.
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.
COSMIC
Cancer Hotspots
Somatic evidence
211 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57264120, n = 211 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 4 met · 8 not met · 9 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PM1 (moderate): p.Asp842 is located in the activation loop (exon 18) of the PDGFRA tyrosine kinase domain, a critical functional domain and statistically significant mutational hotspot.
PM2 (moderate): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
PS3 (moderate): Multiple independent functional studies demonstrate that PDGFRA D842V is a constitutively activating, gain-of-function mutation with ligand-independent autophosphorylation and transforming activity. Strength is limited to moderate because all functional evidence derives from somatic GIST contexts.
PP3 (supporting): REVEL predicts a damaging effect (score 0.861). BayesDel is intermediate (0.343) and SpliceAI predicts no splicing impact (0.02), but REVEL provides supporting computational evidence of pathogenicity.
Classification: Likely Pathogenic. Three moderate criteria (PM1 + PM2 + PS3) and one supporting criterion (PP3) meet the generic ACMG/AMP 2015 threshold for Likely Pathogenic (3 moderate, or 2 moderate + 2 supporting).
Caveat: All functional and prevalence evidence is derived from somatic (GIST) contexts. This variant has not been observed in any germline case. A definitive germline classification is constrained by this limitation.
No criteria match.
Met · 4
PS3 ModeratePDGFRA D842V has been characterized as a gain-of-function, constitutively activating mutation in multiple independent functional studies across several cell line systems (CHO, 293T, Ba/F3), demonstrating ligand-independent autophosphorylation and transforming activity. Five independent publications confirmed constitutive kinase activation. All functional evidence derives from somatic GIST contexts; no germline-specific functional studies are available, which limits the strength applied. Details ▾Hide ▴
Evidence considered
- Constitutive ligand-independent PDGFRA autophosphorylation in CHO cells (PMID:12522257)
- Constitutive activation and autonomous Ba/F3 proliferation confirmed
- imatinib-resistant (PMID:12949711)
- D842V accounts for 181/289 published PDGFRA-mutant GISTs
- confirmed activating in vitro and in vivo
- imatinib-resistant (PMID:15928335)
- Acquired D842V mutation confers imatinib resistance
- sensitive to PKC412 (PMID:15685537)
- D842V resistant to AMN107 in Ba/F3 cells (PMID:16030188)
- D842V used as positive control for activated PDGFRα in 293T functional assays (PMID:17087943)
Still missing
- All functional evidence is from somatic (GIST tumor) contexts. No germline-specific functional study has been performed for D842V.
Sources
PM1 ModerateAsp842 is located in the activation loop (exon 18) of the PDGFRA tyrosine kinase domain, a critical functional domain. This residue lies within a statistically significant mutational hotspot and is the most frequently mutated codon in PDGFRA-driven GIST. Details ▾Hide ▴
Evidence considered
- Statistically significant hotspot at this residue (hotspots)
- Asp842 mutations account for the majority of PDGFRA alterations in GIST
- D842V alone represents 62.6% of published PDGFRA-mutant GISTs (PMID:15928335)
Sources
PM2 ModerateThis variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0, meeting the PM2 threshold for absence from population databases (allele frequency <0.1%). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada v1.0
Sources
PP3 SupportingREVEL predicts a damaging effect (score 0.861, well above the 0.5 threshold). BayesDel score is 0.343 (intermediate). SpliceAI predicts no splicing impact (max delta 0.02). Multiple in silico lines are mixed, but REVEL strongly supports pathogenicity, providing supporting-level evidence. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.861 (damaging)
- BayesDel score: 0.342708 (intermediate)
- SpliceAI max delta: 0.02 (no splicing impact)
Sources
Not met · 8 · evaluated, threshold not reached
PS4 D842V is the most common PDGFRA mutation in sporadic GIST (181/289 published cases) and is reported 211 times in COSMIC. However, all case observations are somatic; no germline case with this variant has been reported. PS4 requires significantly increased prevalence in affected individuals versus controls in a germline context, which cannot be established from somatic data alone. Details ▾Hide ▴
Evidence considered
- D842V observed in 181/289 (62.6%) published PDGFRA-mutant GISTs (PMID:15928335)
- COSMIC reports 211 somatic observations (COSV57264120)
Still missing
- No germline case observations
- all prevalence data are somatic.
Sources
PP5 ClinVar aggregate classification for this variant is Uncertain significance (1 clinical laboratory). The OMIM submission classifies it as Pathogenic, but lacks assertion criteria and is based on literature only with somatic origin. This does not meet the threshold for a reputable source recently reporting the variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar VUS (1 submitter)
- OMIM submission Pathogenic but no assertion criteria
- somatic origin.
Sources
BA1 This variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada). Allele frequency is 0.0%, well below the BA1 threshold of >1%. Details ▾Hide ▴
BS1 This variant is absent from all population databases. Allele frequency is 0.0%, well below the BS1 threshold of >0.3%. Details ▾Hide ▴
BS3 Well-established functional studies consistently demonstrate a gain-of-function effect: constitutive autophosphorylation, ligand-independent kinase activation, and transforming activity. These findings are not supportive of a benign interpretation. Details ▾Hide ▴
Evidence considered
- Constitutive ligand-independent activation in CHO
- 293T
- and Ba/F3 cells
- Transforming activity demonstrated by IL-3 independence in Ba/F3 cells
Sources
BP1 PDGFRA germline disease is caused by gain-of-function missense mutations (e.g., Y555C in familial GIST), not solely by truncating variants. BP1 is not applicable when missense variants are a known disease mechanism. Details ▾Hide ▴
Evidence considered
- PDGFRA germline missense mutations (Y555C) cause familial GIST
- gain-of-function is the established disease mechanism.
Sources
BP4 REVEL predicts a damaging effect (0.861). While BayesDel is intermediate (0.343) and SpliceAI shows no splicing impact, the computational evidence overall does not support a benign interpretation. REVEL strongly supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL 0.861 (damaging)
- BayesDel 0.343 (intermediate)
- SpliceAI 0.02 (no impact). Mixed
- not supportive of benign.
Sources
BP6 No reputable source reports this variant as benign. ClinVar aggregate classification is Uncertain significance. Details ▾Hide ▴
Not assessed · 9 · no assessment recorded
PS2 No de novo data are available for this variant. No family studies or parent-of-origin testing results were identified. Details ▾Hide ▴
Still missing
- No de novo testing data
- no parental genotypes available.
PM6 No de novo data are available. PM6 cannot be applied without confirmed de novo occurrence with maternity/paternity confirmation. Details ▾Hide ▴
Still missing
- No de novo testing data available.
PP1 No segregation data are available for this variant. No family studies were identified. Details ▾Hide ▴
Still missing
- No family segregation data available.
PP2 HCI prior score is not available for PDGFRA. The gene is not included in the HCI prior database, so the proportion of benign missense variants in this gene cannot be calculated. Details ▾Hide ▴
Still missing
- HCI prior score unavailable for PDGFRA.
PP4 No patient phenotype data or clinical information was provided for this case. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
- No patient phenotype data provided.
BS2 No data on healthy adult carriers are available. The variant is absent from gnomAD, so no observation in a healthy adult has been documented. Details ▾Hide ▴
Still missing
- No healthy adult carrier data.
BS4 No segregation data are available for this variant. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP2 No data on trans configuration with a known pathogenic variant are available. Details ▾Hide ▴
Still missing
- No trans phase data available.
BP5 No data on an alternate molecular basis for disease in a case harboring this variant are available. Details ▾Hide ▴
Still missing
- No data on alternate molecular diagnoses.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_006206.6:c.2525A>T is a missense variant (p.Asp842Val) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Details ▾Hide ▴
Evidence considered
- Missense variant in exon 18
- not a null variant.
Sources
pvs1_variant_assessment
PS1 N/APS1 applies when the same amino acid change results from a different nucleotide change that has been established as pathogenic. No alternative nucleotide change producing p.Asp842Val with an established pathogenic classification is available. Details ▾Hide ▴
Evidence considered
- Only one nucleotide substitution (c.2525A>T) is known to produce p.Asp842Val.
PM5 N/ANo comparator missense variants at codon 842 with a confirmed pathogenic classification were identified. Automated candidate harvesting was unable to confirm classic same-residue PM5 semantics. Details ▾Hide ▴
Evidence considered
- No qualifying same-residue pathogenic comparator variants identified.
Sources
pm5_candidates
BP7 N/AThis variant is a missense substitution (c.2525A>T, p.Asp842Val), not a synonymous variant. BP7 only applies to synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion. Under the generic ACMG framework, no PS5 rule is defined. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PDGFRA
- Transcript
- NM_006206.6
- Coding (HGVS c.)
- NM_006206.6:c.2525A>T
- Protein (HGVS p.)
- NP_006197.1:p.(Asp842Val)
- GRCh38
- chr4:54285926 A>T
- GRCh37
- chr4:55152093 A>T
- ClinVar
- 13543
- COSMIC
- COSV57264120
Gene diagram
Every interpreted variant in PDGFRA, mapped onto the exon structure of NM_006206.6. Select a row to find it on the plot.
PDGFRANM_006206.6
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PDGFRA
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
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
Other predictors
- REVEL
- 0.861
- BayesDel
- 0.343
How the predictions were used
PP3 SupportingREVEL predicts a damaging effect (score 0.861, well above the 0.5 threshold). BayesDel score is 0.343 (intermediate). SpliceAI predicts no splicing impact (max delta 0.02). Multiple in silico lines are mixed, but REVEL strongly supports pathogenicity, providing supporting-level evidence. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.861 (damaging)
- BayesDel score: 0.342708 (intermediate)
- SpliceAI max delta: 0.02 (no splicing impact)
Sources
BP4 REVEL predicts a damaging effect (0.861). While BayesDel is intermediate (0.343) and SpliceAI shows no splicing impact, the computational evidence overall does not support a benign interpretation. REVEL strongly supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL 0.861 (damaging)
- BayesDel 0.343 (intermediate)
- SpliceAI 0.02 (no impact). Mixed
- not supportive of benign.
Sources
BP7 N/AThis variant is a missense substitution (c.2525A>T, p.Asp842Val), not a synonymous variant. BP7 only applies to synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.861. BayesDel score = 0.342708.
7 paper records listed. 6 cited in the classification.
Cited in the classification
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PMID 12522257 ↗PDGFRA activating mutations in gastrointestinal stromal tumors.Heinrich MC et al. · 2003 Jan 31PDGFRA D842V identified as a somatic activating mutation in exon 18 of KIT-wildtype GISTs. Constitutive ligand-independent autophosphorylation demonstrated in transiently transfected CHO cells. D842V was the most common PDGFRA mutation found (8 of 14 PDGFRA-mutant GISTs).→ PS3 Names this variant
Source detail
Two of the KIT-WT GISTs had an identical PDGFRA missense mutation, leading to substitution of valine for the highly conserved aspartic acid at codon 842 (PDGFRA D842V).
Location Results paragraph 2; Table 1; Figure 2
Context Transient transfection in CHO cells; immunoblotting for phosphotyrosine and PDGFRA
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PMID 12949711 ↗Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors.Hirota S et al. · 2003 SepPDGFRA Asp842Val identified as a gain-of-function mutation in 3 of 8 GISTs without KIT mutations. Demonstrated strong constitutive tyrosine phosphorylation in 293T cells without ligand stimulation. Ba/F3 cells expressing D842V grew autonomously without IL-3. D842V was resistant to imatinib, showing only partial inhibition at 10 μmol/L.→ PS3 Names this variant
Source detail
PDGFR α with 842-Asp to Val substitution was phosphorylated strongly on tyrosine without the addition of human PDGF-AA.
Location Results section; Table 1; Figures 3-5
Context Transient transfection in 293T human embryonic kidney cells; stable transfection in Ba/F3 murine lymphoid cells; tritium thymidine incorporation assay
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PMID 15685537 ↗Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants.Investigated mechanisms of imatinib resistance in 26 progressive GIST patients. One patient with an initial KIT G565R mutation acquired a secondary PDGFRA D842V mutation at progression. D842V was confirmed imatinib-resistant in Ba/F3 cells but sensitive to PKC412. The D842V mutant showed the highest cellular IC50 among all tested mutants.→ PS3 Names this variant
Source detail
One patient (case 25) with an original KIT G565R mutation acquired a D842V point mutation in PDGFRA that was not detectable in the primary tumor from this patient.
Location Results; Table 2; Figure 4
Context Ba/F3 cells stably expressing PDGFRA-D842V; dose-response curves for imatinib and PKC412
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PMID 15928335 ↗PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib.Comprehensive catalog of PDGFRA mutations in 1,105 GISTs. D842V was the most common mutation, representing 181 of 289 (62.6%) published PDGFRA-mutant GISTs. D842V confirmed as constitutively activating in CHO cells and imatinib-resistant in vitro (IC50 > 1 μM). Transient expression in CHO cells showed ligand-independent tyrosine phosphorylation for all D842-mutant isoforms.→ PS3 → PM1 Names this variant
Source detail
the single most common PDGFRA mutation in GISTs is the substitution D842V (62.6%).
Location Table 1; Results; Discussion
Context Transient transfection in CHO cells; stable Ba/F3 cell lines; XTT proliferation assay; immunoblotting
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PMID 16030188 ↗The small molecule tyrosine kinase inhibitor AMN107 inhibits TEL-PDGFRbeta and FIP1L1-PDGFRalpha in vitro and in vivo.Evaluated AMN107 (nilotinib) against PDGFR fusion kinases. PDGFRα D842V was tested as an imatinib-resistant control. Ba/F3 cells expressing PDGFRα D842V were resistant to AMN107 at concentrations up to 1 μM, confirming the drug-resistant nature of this mutation.→ PS3 Names this variant
Source detail
Ba/F3 cells expressing PDGFRα D842V were resistant to AMN107, because growth was not inhibited at concentrations up to 1 μM.
Location Table 1; Table 3; Results
Context Ba/F3 murine pro-B-cell line; retroviral transduction; Celltiter96 AqueousOne proliferation assay
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PMID 17087943 ↗Intestinal neurofibromatosis is a subtype of familial GIST and results from a dominant activating mutation in PDGFRA.de Raedt T et al. · 2006 DecReported a germline PDGFRA Y555C mutation causing familial intestinal neurofibromatosis/GIST. PDGFRA D842V was used as a positive control for activated (phosphorylated) PDGFRα in 293T and Ba/F3 functional assays. D842V showed strong autophosphorylation in both cell lines and conferred IL-3-independent growth in Ba/F3 cells. D842V was confirmed imatinib-resistant, while Y555C was imatinib-sensitive.→ PS3 Names this variant
Source detail
A PDGFRα with a known activating somatic mutation (D842V) common in sporadic GIST was used as a positive control for activated (phosphorylated) PDGFRα.
Location Results; Figures 3 and 4
Context Transient transfection in 293T cells; stable retroviral transduction in Ba/F3 cells; Western blot for phospho-PDGFRα
Other recorded publications
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PMID 23852704 ↗Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update.Duffy MJ et al. · 2014European Group on Tumor Markers (EGTM) 2014 guidelines update on biomarkers in gastrointestinal cancers, including GIST. Discusses KIT and PDGFRA mutation testing as a diagnostic and prognostic biomarker in GIST at the gene level. The specific variant NM_006206.6:c.2525A>T (p.Asp842Val / D842V) was not identified in this paper.Does not name this variant
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 0.020
Open source ↗
ClinVar
1 Uncertain significance
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/13543/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/4-55152093-A-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr4-54285926-A-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/4-54285926-A-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006206.6%3Ac.2525…
- OncoKB ↗www.oncokb.org/gene/PDGFRA/D842V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=122274916
- Cancer hotspots ↗www.cancerhotspots.org/
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 has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 13543)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.861. BayesDel score = 0.342708.
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; COSV57264120, n = 211 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.