About PDGFRA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PDGFRA c.1780G>A, p.(Val594Met)
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_006206.5:c.1780G>A is absent from gnomAD v2.1 and v4.1 population databases, meeting the generic ACMG threshold for PM2 (allele frequency <0.1% in population controls).
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: PM2 supporting; combination = 1 supporting, 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.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance.
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 does not lie 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.
29 criteria with recorded statuses: 1 met · 23 not met · 0 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
NM_006206.5:c.1780G>A (p.Val594Met) in PDGFRA is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).
This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (Labcorp Genetics, Ambry Genetics); no expert panel or reputable source has classified it as pathogenic or benign.
Computational predictions are conflicting: REVEL score is borderline (0.55), BayesDel is in the benign range (0.089), and SpliceAI predicts no splicing impact (max delta 0.00). PP3 and BP4 are not met due to this conflict.
No functional studies (PS3/BS3), segregation data (PP1/BS4), de novo occurrences (PS2/PM6), or case-control data (PS4) were identified for this variant. No pathogenic missense variants at the same residue (PM5/PS1) or codon (PS5) were found.
PVS1 is not applicable as the variant is missense, not a null variant. BP7 is not applicable as the variant is nonsynonymous. BP3, PM3, and PM4 are not applicable by variant type or inheritance pattern.
No criteria match.
Met · 1
PM2 SupportingNM_006206.5:c.1780G>A is absent from gnomAD v2.1 and v4.1 population databases, meeting the generic ACMG threshold for PM2 (allele frequency <0.1% in population controls). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- absent from gnomAD v4.1 (exomes)
- absent from gnomAD-Canada v1.0.
Sources
Not met · 23 · evaluated, threshold not reached
PS1 No alternative nucleotide change at codon 594 resulting in the same amino acid substitution (Val594Met) has been established as pathogenic. PS1 requires a different nucleotide change at the same codon producing the identical missense change with an accepted pathogenic classification. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic comparator variant identified
- PM5 candidate search returned zero candidates.
Still missing
- No ClinVar pathogenic variant entries at codon 594 with a different nucleotide change.
Sources
pm5_candidates
PS2 No de novo occurrence of NM_006206.5:c.1780G>A with confirmed paternity and maternity has been reported in the literature or databases. Details ▾Hide ▴
Evidence considered
- Exploratory literature search identified no de novo reports for this variant.
Still missing
- No trio-based sequencing studies reporting this variant as de novo.
PS3 No well-established in vitro or in vivo functional studies demonstrating a damaging effect on PDGFRA protein function have been identified for p.Val594Met. Details ▾Hide ▴
Evidence considered
- OncoKB reports Unknown Oncogenic Effect for this variant
- no functional studies found in exploratory literature search
- no PMID-specific functional data available.
Still missing
- Absence of kinase assay
- growth factor signaling
- or other functional characterization of p.Val594Met.
Sources
23852704
PS4 The variant is absent from gnomAD population databases, but no case-control or cohort studies demonstrate statistically significant enrichment of NM_006206.5:c.1780G>A in affected individuals over controls. PS4 requires a higher prevalence in affected individuals that is statistically significant. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1
- ClinVar reports VUS classification from two clinical laboratories
- no published case-control or cohort data with statistical comparison.
Still missing
- No case-control or cohort frequency data comparing variant prevalence in GIST or other PDGFRA-associated disease cohorts vs general population.
Sources
PM1 Residue Val594 is not identified as a statistically significant mutational hotspot by Cancer Hotspots, is absent from COSMIC, and has not been demonstrated to lie within a critical functional domain without benign variation in PDGFRA. Although PDGFRA has known functional domains relevant to GIST, the specific residue lacks supporting evidence for PM1. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue not significant
- COSMIC: variant not found
- no literature establishing residue 594 as a critical functional domain residue with absence of benign variation.
Still missing
- No evidence that Val594 is a recurrent somatic or germline hotspot
- no domain-specific constraint data for this residue.
PM5 No pathogenic missense variant at the same residue (Val594) with a different amino acid change has been identified. The PM5 candidate search returned zero comparators at residue 594. Details ▾Hide ▴
Evidence considered
- Zero same-residue comparator candidates identified
- no ClinVar pathogenic variant entries at codon 594 with a different amino acid change.
Still missing
- Absence of any established pathogenic missense variant at residue 594.
Sources
pm5_candidates
PM6 No assumed de novo occurrence of NM_006206.5:c.1780G>A has been reported (without confirmation of paternity and maternity). Details ▾Hide ▴
Evidence considered
- No de novo reports found in literature or database review
- exploratory search identified no relevant reports.
Still missing
- No reports of this variant occurring de novo in affected probands.
PP1 No cosegregation data for NM_006206.5:c.1780G>A with PDGFRA-associated disease in multiple affected family members has been reported. Details ▾Hide ▴
Evidence considered
- Exploratory literature and database search identified no family studies or cosegregation data.
Still missing
- No family-based cosegregation analysis for this variant.
PP2 HCI prior data is unavailable for PDGFRA (gene not supported), precluding confirmation of a low rate of benign missense variation. Without this, PP2 cannot be applied for this missense variant. Details ▾Hide ▴
Evidence considered
- HCI prior: gene not supported
- unable to establish low benign missense rate for PDGFRA.
Still missing
- No gene-level constraint metric (HCI prior) available for PDGFRA to assess benign missense variation rate.
PP3 Computational evidence is conflicting: REVEL score 0.55 is borderline (just above the 0.5 threshold), BayesDel score 0.089 is in the benign range (<0.27), and SpliceAI max delta is 0.00 (no predicted splice impact). Multiple lines of computational evidence do not uniformly support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.55 (borderline pathogenic)
- BayesDel: 0.089 (suggests benign)
- SpliceAI max delta: 0.00 (no splice impact).
Still missing
- Conflicting in silico predictions
- REVEL borderline
- BayesDel benign.
Sources
PP4 No patient phenotype or family history data specific to a disease with a single genetic etiology are available for this variant. PP4 requires that the proband's phenotype or family history be highly specific for a disease with a single genetic cause. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data for the proband carrying this variant available in the evidence record.
Still missing
- Absence of proband phenotype or family history information.
PP5 ClinVar reports NM_006206.5:c.1780G>A as Uncertain significance (criteria provided, single submitter) from two clinical laboratories. No reputable source has classified this variant as pathogenic. PP5 requires a reputable source to have reported the variant as pathogenic with evidence not independently available. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance (2 submitters)
- no expert panel or reputable source pathogenicity assertion.
Sources
clinvar ↗28492532
BA1 NM_006206.5:c.1780G>A is absent from gnomAD v2.1 and v4.1. BA1 requires an allele frequency >1% in any population. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1
- allele frequency 0%.
Sources
BS1 NM_006206.5:c.1780G>A is absent from gnomAD v2.1 and v4.1. BS1 requires an allele frequency >0.3% in any population. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1
- allele frequency 0%.
Sources
BS2 NM_006206.5:c.1780G>A is absent from gnomAD population databases. BS2 requires observation in healthy adults at a significant frequency (particularly for disorders with full penetrance presenting early in life). The variant has not been observed in any population cohort. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD datasets
- no observation in healthy adult carriers.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect on PDGFRA protein function have been identified for p.Val594Met. BS3 requires robust functional evidence showing the variant has no deleterious impact. Details ▾Hide ▴
Evidence considered
- OncoKB reports Unknown Oncogenic Effect
- no functional studies showing neutral effect found in exploratory search.
Still missing
- No functional studies characterizing the effect of p.Val594Met on PDGFRA kinase activity or downstream signaling.
Sources
23852704
BS4 No segregation data are available for NM_006206.5:c.1780G>A to demonstrate lack of cosegregation with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No family-based segregation studies identified.
Still missing
- Absence of segregation analysis in families with PDGFRA-associated disease.
BP1 PDGFRA-associated disease (e.g., GIST) is primarily driven by gain-of-function missense variants rather than exclusively by truncating variants. BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease, which is not the case for PDGFRA. Details ▾Hide ▴
Evidence considered
- PDGFRA disease mechanism in GIST is gain-of-function via missense mutations
- truncating variants are not the exclusive pathogenic mechanism.
BP2 No evidence that NM_006206.5:c.1780G>A has been observed in cis or in trans with a pathogenic PDGFRA variant. While BP2 primarily applies to recessive disorders (observed in trans), the variant has no co-occurrence data of any kind with another pathogenic variant. Details ▾Hide ▴
Evidence considered
- No co-occurrence data with pathogenic variants in PDGFRA.
Still missing
- No phase information for this variant relative to other PDGFRA variants.
BP4 Computational evidence is conflicting. While BayesDel (0.089, benign range) and SpliceAI (max delta 0.00) suggest no impact, REVEL score of 0.55 is borderline pathogenic (>0.5). BP4 requires multiple lines of computational evidence to uniformly suggest no impact on the gene product, which is not satisfied due to the conflicting REVEL score. Details ▾Hide ▴
Evidence considered
- REVEL: 0.55 (borderline pathogenic)
- BayesDel: 0.089 (suggests benign)
- SpliceAI: 0.00 (no splicing impact). Conflicting predictions preclude BP4.
Still missing
- REVEL score conflicts with other benign predictions
- limited in silico consensus.
Sources
BP5 No evidence is available demonstrating that NM_006206.5:c.1780G>A has been observed in a case with an alternate molecular basis for disease that could explain the phenotype. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis data available for individuals carrying this variant.
Still missing
- No data on co-occurring pathogenic variants in other genes that could explain the phenotype.
BP6 ClinVar reports NM_006206.5:c.1780G>A as Uncertain significance, not benign. BP6 requires a reputable source to have classified the variant as benign with evidence not independently available. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance
- no reputable source reports as benign.
Sources
PS5 No alternative nucleotide change at codon 594 predicted to produce the Val594Met substitution has been established as pathogenic in ClinVar or the literature. PS5 also requires that the alternative variant be more severe (e.g., a different missense classified as pathogenic). Details ▾Hide ▴
Evidence considered
- No same-codon pathogenic variants identified
- PM5 candidate search returned no comparators at residue 594.
Still missing
- No pathogenic missense variants at codon 594 with a different nucleotide change.
Sources
pm5_candidates
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_006206.5:c.1780G>A is a missense variant (p.Val594Met); PVS1 is restricted to null variants (nonsense, frameshift, canonical ±1,2 splice consensus). The variant does not fall into any PVS1 bucket per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null variant
- PVS1 framework does not apply.
Sources
PM3 N/APM3 applies to recessive disorders (variant detected in trans with a pathogenic variant). PDGFRA-associated disease is inherited in an autosomal dominant manner with incomplete penetrance. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length changes due to non-repeat region deletions/insertions or stop-loss variants. This variant is a single nucleotide substitution producing a missense change. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions. This variant is a single nucleotide substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_006206.5:c.1780G>A is a missense variant (p.Val594Met), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous variants.
Identifiers
- Gene
- PDGFRA
- Transcript
- NM_006206.5
- Coding (HGVS c.)
- NM_006206.5:c.1780G>A
- Protein (HGVS p.)
- NP_006197.1:p.(Val594Met)
- GRCh38
- chr4:54274967 G>A
- GRCh37
- chr4:55141134 G>A
- ClinVar
- 1970330, 1519216
Gene diagram
Every interpreted variant in PDGFRA, mapped onto the exon structure of NM_006206.5. Select a row to find it on the plot.
PDGFRANM_006206.5
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
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.550
- BayesDel
- 0.089
How the predictions were used
PP3 Computational evidence is conflicting: REVEL score 0.55 is borderline (just above the 0.5 threshold), BayesDel score 0.089 is in the benign range (<0.27), and SpliceAI max delta is 0.00 (no predicted splice impact). Multiple lines of computational evidence do not uniformly support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.55 (borderline pathogenic)
- BayesDel: 0.089 (suggests benign)
- SpliceAI max delta: 0.00 (no splice impact).
Still missing
- Conflicting in silico predictions
- REVEL borderline
- BayesDel benign.
Sources
BP4 Computational evidence is conflicting. While BayesDel (0.089, benign range) and SpliceAI (max delta 0.00) suggest no impact, REVEL score of 0.55 is borderline pathogenic (>0.5). BP4 requires multiple lines of computational evidence to uniformly suggest no impact on the gene product, which is not satisfied due to the conflicting REVEL score. Details ▾Hide ▴
Evidence considered
- REVEL: 0.55 (borderline pathogenic)
- BayesDel: 0.089 (suggests benign)
- SpliceAI: 0.00 (no splicing impact). Conflicting predictions preclude BP4.
Still missing
- REVEL score conflicts with other benign predictions
- limited in silico consensus.
Sources
BP7 N/ANM_006206.5:c.1780G>A is a missense variant (p.Val594Met), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.55. BayesDel score = 0.0893606.
4 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
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. · 2014No paper-specific finding is recorded.
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015No paper-specific finding is recorded.
-
PMID 22685257 ↗The UK NEQAS for Molecular Genetics scheme for gastrointestinal stromal tumour: findings and recommendations following four rounds of circulation.Wong NA et al. · 2012No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
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 0.000
Open source ↗
ClinVar
2 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/1519216/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/4-55141134-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr4-54274967-G-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006206.5%3Ac.1780…
- OncoKB ↗www.oncokb.org/gene/PDGFRA/V594M
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PDGFRA+c.1780G%3EA
- 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.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 1519216)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.55. BayesDel score = 0.0893606.
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 does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.