NM_006206.6:c.2525A>T

PDGFRA · NP_006197.1:p.(Asp842Val) · NM_006206.6

GRCh37: chr4:55152093 A>T · GRCh38: chr4:54285926 A>T

Gene: PDGFRA Transcript: NM_006206.6

Final call

Likely Pathogenic

PS3 moderate PM1 moderate PM2 moderate PP3 supporting

Variant details

Gene

PDGFRA

Transcript

NM_006206.6

Protein

NP_006197.1:p.(Asp842Val)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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.	pvs1_variant_assessment
PS1	N/A	PS1 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.
PS2	Not assessed	No de novo data are available for this variant. No family studies or parent-of-origin testing results were identified.
PS3	Met	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.	PMID:12522257 PMID:12949711 PMID:15928335 PMID:15685537 PMID:16030188 PMID:17087943
PS4	Not met	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.	PMID:15928335
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion. Under the generic ACMG framework, no PS5 rule is defined.
PM1	Met	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.	PMID:15928335
PM2	Met	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%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No 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.	pm5_candidates
PM6	Not assessed	No de novo data are available. PM6 cannot be applied without confirmed de novo occurrence with maternity/paternity confirmation.
PP1	Not assessed	No segregation data are available for this variant. No family studies were identified.
PP2	Not assessed	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.
PP3	Met	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.	revel bayesdel spliceai
PP4	Not assessed	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.
PP5	Not met	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.	clinvar
BA1	Not met	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%.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from all population databases. Allele frequency is 0.0%, well below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data on healthy adult carriers are available. The variant is absent from gnomAD, so no observation in a healthy adult has been documented.
BS3	Not met	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.	PMID:12522257 PMID:12949711 PMID:15928335
BS4	Not assessed	No segregation data are available for this variant.
BP1	Not met	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.	PMID:17087943
BP2	Not assessed	No data on trans configuration with a known pathogenic variant are available.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not assessed	No data on an alternate molecular basis for disease in a case harboring this variant are available.
BP6	Not met	No reputable source reports this variant as benign. ClinVar aggregate classification is Uncertain significance.	clinvar
BP7	N/A	This 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.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.