NM_006206.6:c.2524_2526delinsCGA

PDGFRA · NP_006197.1:p.(Asp842Arg) · NM_006206.6

GRCh37: chr4:55152092 GAC>CGA · GRCh38: chr4:54285925 GAC>CGA

Gene: PDGFRA Transcript: NM_006206.6

Final call

VUS

PM1 moderate PM2 moderate

Variant details

Gene

PDGFRA

Transcript

NM_006206.6

Protein

NP_006197.1:p.(Asp842Arg)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	This 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.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No 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.	clinvar
PS2	N/A	No de novo data available; no parental testing information provided.
PS3	Not met	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.	oncokb
PS4	N/A	No case-control or cohort data available to assess variant prevalence in affected individuals versus controls.
PS5	N/A	PS5 is not a standard criterion defined in the ACMG/AMP 2015 framework (PMID:25741868). This criterion is not applicable under generic ACMG adjudication.
PM1	Met	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.	oncokb
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 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.
PM5	N/A	No 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.	pm5_candidates clinvar
PM6	N/A	No de novo data available; no parental testing or confirmed maternity/paternity information.
PP1	N/A	No cosegregation data available; no family studies with this variant.
PP2	N/A	PP2 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.
PP3	N/A	Multiple 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.	spliceai
PP4	N/A	No patient phenotype or clinical history data available to evaluate specificity for a PDGFRA-associated disorder.
PP5	N/A	No reputable source (e.g., clinical diagnostic laboratory, expert panel) has reported this specific variant as pathogenic. The variant is absent from ClinVar.	clinvar
BA1	Not met	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).	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	N/A	No homozygous or compound heterozygous observations in population databases; no evidence of healthy adult carriers. BS2 cannot be assessed.
BS3	N/A	No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing were identified.
BS4	N/A	No segregation data available; cannot assess lack of cosegregation with disease.
BP1	N/A	BP1 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.	oncokb
BP2	N/A	No observation of this variant in trans with a known pathogenic variant in PDGFRA; no data to evaluate BP2.
BP3	N/A	BP3 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.
BP4	N/A	No 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.	spliceai
BP5	N/A	No observation of this variant in a case with an alternate molecular basis for disease; no data to evaluate BP5.
BP6	N/A	No reputable source has reported this variant as benign; absent from ClinVar.	clinvar
BP7	N/A	BP7 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.

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