About PDGFRA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PDGFRA c.2524_2526delinsCGA, p.(Asp842Arg)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM1Moderate
PM1 · moderate
The variant alters Asp842 in the activation loop of the PDGFRA tyrosine kinase domain (exon 18). This residue is a statistically significant mutational hotspot (Cancer Hotspots confirmed) and lies within a critical well-established functional domain without benign variation.
PM2Moderate
PM2 · moderate
Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (allele frequency 0%), which is below the PM2 threshold of <0.1% for a rare variant in a gene with established disease association.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate; combination = 2 moderate, which maps to VUS.
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.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PDGFRA, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in a diverse range of cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant 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.
28 criteria with recorded statuses: 2 met · 3 not met · 0 not assessed · 23 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_006206.6:c.2524_2526delinsCGA (p.Asp842Arg) in PDGFRA is an in-frame deletion-insertion altering the kinase activation loop residue Asp842, a statistically significant mutational hotspot (PM1). The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2).
No other pathogenic or likely pathogenic criteria were met. PVS1 is not applicable (in-frame variant, not a null variant). PS3 functional evidence was not established: although D842R is annotated as Likely Oncogenic by OncoKB and lies in a hotspot, no variant-specific reviewed functional data with citations were identified in the literature packet. No segregation, de novo, in silico, or clinical case data were available.
Under the generic ACMG/AMP 2015 classification framework (PMID:25741868), the combination of two moderate criteria (PM1 + PM2) without additional supporting evidence is insufficient to reach the Likely Pathogenic threshold, which requires ≥3 moderate criteria or ≥2 moderate with ≥2 supporting. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM1 ModerateThe variant alters Asp842 in the activation loop of the PDGFRA tyrosine kinase domain (exon 18). This residue is a statistically significant mutational hotspot (Cancer Hotspots confirmed) and lies within a critical well-established functional domain without benign variation. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue D842 is a statistically significant hotspot
- OncoKB: Likely Oncogenic
- located in kinase activation loop
Sources
PM2 ModerateVariant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (allele frequency 0%), which is below the PM2 threshold of <0.1% for a rare variant in a gene with established disease association. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- Absent from gnomAD v4.1 (exomes/genomes)
- Absent from gnomAD-Canada v1.0
Sources
Not met · 3 · evaluated, threshold not reached
PS3 PDGFRA D842R is annotated as Likely Oncogenic (Likely Gain-of-function) by OncoKB and residue Asp842 is a statistically significant cancer hotspot, consistent with a known activating mutation in the kinase activation loop. However, OncoKB did not identify variant-specific reviewed functional evidence (not_reviewed=true, is_variant_specific=false) and no PMIDs with functional assay data for this exact variant were identified in the literature packet. Independent functional studies meeting germline PS3 thresholds are not available. Details ▾Hide ▴
Evidence considered
- OncoKB: Likely Oncogenic
- Likely Gain-of-function (not_reviewed
- not variant-specific)
- Cancer Hotspots: residue D842 is a statistically significant hotspot
Still missing
- No variant-specific functional assay data identified in literature packet
- OncoKB annotation lacks expert review and variant-specific citations
Sources
BA1 The variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada). Allele frequency is 0%, which does not exceed the BA1 threshold of >1% (or >5% for some frameworks). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- gnomAD-Canada v1.0: absent
Sources
BS1 The variant is absent from all population databases (allele frequency 0%), which is well below the BS1 threshold of >0.3%. Population data does not support a benign interpretation. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- gnomAD-Canada v1.0: absent
Sources
Not applicable · 23· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is an in-frame deletion-insertion (c.2524_2526delinsCGA) resulting in a single amino acid substitution p.(Asp842Arg); it does not fall into the ClinGen SVI PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants). Generic PVS1 framework assessment is not applicable per PMC6185798. Details ▾Hide ▴
Evidence considered
- Variant is an in-frame delins producing p.Asp842Arg
- not a null variant
- PVS1 variant assessment: bucket='other'
- apply_generic_pvs1_framework=false
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ANo alternative nucleotide change at amino acid position Asp842 with an established pathogenic classification was identified in ClinVar or available literature to serve as a PS1 comparator. Details ▾Hide ▴
Evidence considered
- ClinVar search: no variants at this residue with a pathogenic classification found
Sources
PS2 N/ANo de novo data available; no parental testing information provided. Details ▾Hide ▴
No further detail was recorded.
PS4 N/ANo case-control or cohort data available to assess variant prevalence in affected individuals versus controls. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to in-frame deletions or insertions that change protein length in a non-repeat region, or stop-loss variants. This variant (c.2524_2526delinsCGA) deletes 3 nucleotides and inserts 3 nucleotides, resulting in no net change in protein length. It produces a single amino acid substitution p.(Asp842Arg) and is functionally equivalent to a missense variant. Details ▾Hide ▴
Evidence considered
- c.2524_2526delinsCGA: 3 bp deleted
- 3 bp inserted
- protein length unchanged
PM5 N/ANo alternative pathogenic missense variant at the same amino acid residue (Asp842) was identified in ClinVar to serve as a PM5 comparator. The automated PM5 candidate search confirmed no eligible comparators. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates identified
- ClinVar: variant absent
- no comparators at D842
Sources
pm5_candidatesclinvar ↗
PM6 N/ANo de novo data available; no parental testing or confirmed maternity/paternity information. Details ▾Hide ▴
No further detail was recorded.
PP1 N/ANo cosegregation data available; no family studies with this variant. Details ▾Hide ▴
No further detail was recorded.
PP2 N/APP2 requires gene-level missense constraint data (e.g., gnomAD missense Z-score) demonstrating a low rate of benign missense variation. No constraint metrics are available for PDGFRA in the evidence packet, and HCI prior data was not found for this gene. Details ▾Hide ▴
Evidence considered
- HCI prior: not found for PDGFRA
- No gnomAD missense Z-score or constraint data available
PP3 N/AMultiple lines of computational evidence cannot be assessed. REVEL and BayesDel are not applicable to indel variants. SpliceAI returned no delta scores. No in silico prediction data is available for this variant. Details ▾Hide ▴
Evidence considered
- REVEL: skipped (not SNV)
- BayesDel: skipped (not SNV)
- SpliceAI: no scores returned
Sources
PP4 N/ANo patient phenotype or clinical history data available to evaluate specificity for a PDGFRA-associated disorder. Details ▾Hide ▴
No further detail was recorded.
PP5 N/ANo reputable source (e.g., clinical diagnostic laboratory, expert panel) has reported this specific variant as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
BS2 N/ANo homozygous or compound heterozygous observations in population databases; no evidence of healthy adult carriers. BS2 cannot be assessed. Details ▾Hide ▴
No further detail was recorded.
BS3 N/ANo well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing were identified. Details ▾Hide ▴
No further detail was recorded.
BS4 N/ANo segregation data available; cannot assess lack of cosegregation with disease. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where only truncating variants cause disease. PDGFRA-associated disorders (e.g., familial GIST) are known to be driven by gain-of-function missense mutations in the kinase domain, making BP1 inapplicable. Details ▾Hide ▴
Evidence considered
- OncoKB: PDGFRA D842R is Likely Gain-of-function
- PDGFRA disease mechanism is missense/activating
- not loss-of-function
Sources
BP2 N/ANo observation of this variant in trans with a known pathogenic variant in PDGFRA; no data to evaluate BP2. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions without known function. This variant is an in-frame delins in the kinase activation loop (a critical functional domain), not a repetitive region. BP3 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant located in kinase activation loop (exon 18)
- a well-established functional domain
BP4 N/ANo in silico computational evidence is available for this indel variant. REVEL, BayesDel, and SpliceAI did not return scores. Multiple lines of computational evidence cannot be evaluated. Details ▾Hide ▴
Evidence considered
- REVEL: not available (not SNV)
- BayesDel: not available (not SNV)
- SpliceAI: no scores returned
Sources
BP5 N/ANo observation of this variant in a case with an alternate molecular basis for disease; no data to evaluate BP5. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ANo reputable source has reported this variant as benign; absent from ClinVar. Details ▾Hide ▴
BP7 N/ABP7 is reserved for synonymous variants not predicted to affect splicing. This variant is a non-synonymous in-frame delins resulting in p.Asp842Arg. BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Variant is non-synonymous (missense-equivalent)
- not synonymous
PS5 N/APS5 is not a standard criterion defined in the ACMG/AMP 2015 framework (PMID:25741868). This criterion is not applicable under generic ACMG adjudication. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PDGFRA
- Transcript
- NM_006206.6
- Coding (HGVS c.)
- NM_006206.6:c.2524_2526delinsCGA
- Protein (HGVS p.)
- NP_006197.1:p.(Asp842Arg)
- GRCh38
- chr4:54285925 GAC>CGA
- GRCh37
- chr4:55152092 GAC>CGA
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in PDGFRA
—
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.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/AMultiple lines of computational evidence cannot be assessed. REVEL and BayesDel are not applicable to indel variants. SpliceAI returned no delta scores. No in silico prediction data is available for this variant. Details ▾Hide ▴
Evidence considered
- REVEL: skipped (not SNV)
- BayesDel: skipped (not SNV)
- SpliceAI: no scores returned
Sources
BP4 N/ANo in silico computational evidence is available for this indel variant. REVEL, BayesDel, and SpliceAI did not return scores. Multiple lines of computational evidence cannot be evaluated. Details ▾Hide ▴
Evidence considered
- REVEL: not available (not SNV)
- BayesDel: not available (not SNV)
- SpliceAI: no scores returned
Sources
BP7 N/ABP7 is reserved for synonymous variants not predicted to affect splicing. This variant is a non-synonymous in-frame delins resulting in p.Asp842Arg. BP7 does not apply. Details ▾Hide ▴
Evidence considered
- Variant is non-synonymous (missense-equivalent)
- not synonymous
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
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
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_006206.6%3Ac.2524_2526delinsCGA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/4-55152092-GAC-CGA?dataset=gn…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr4-54285925-GAC-CGA?dataset…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/4-54285925-GAC-CGA
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006206.6%3Ac.2524…
- OncoKB ↗www.oncokb.org/gene/PDGFRA/D842R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PDGFRA+c.2524_2526delinsCGA
- 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 is absent from ClinVar.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PDGFRA, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in a diverse range of cancers.
Somatic
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant lies in a statistically significant hotspot.