NM_006206.5:c.1988C>T

PDGFRA · NP_006197.1:p.(Ala663Val) · NM_006206.5

GRCh37: chr4:55144159 C>T · GRCh38: chr4:54277992 C>T

Gene: PDGFRA Transcript: NM_006206.5

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

PDGFRA

Transcript

NM_006206.5

Protein

NP_006197.1:p.(Ala663Val)

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_006206.5:c.1988C>T (p.Ala663Val) is a missense variant in exon 14 of PDGFRA, a receptor tyrosine kinase gene.

This variant is absent from gnomAD v2.1 and v4.1 (0/1,607,834 alleles), meeting PM2 at supporting strength.

In silico analysis yields conflicting predictions: REVEL score of 0.755 suggests a damaging effect, but BayesDel (0.21064) and SpliceAI (max delta 0.00) predict a benign/no-impact outcome. Multiple lines of computational evidence do not converge on pathogenicity; PP3 is not met.

BayesDel and SpliceAI independently predict no deleterious effect, meeting BP4 at supporting benign strength.

This variant is absent from ClinVar; no pathogenic or benign classification exists from any expert panel or clinical laboratory. PS1, PS5, PM5, PP5, and BP6 cannot be applied.

No functional studies, de novo reports, case-control data, segregation data, or publications mentioning this specific variant were identified. PS2, PS3, PS4, PM6, PP1, PP4, BS2, BS3, BS4, BP2, and BP5 are not met.

The variant is not located in a statistically significant mutational hotspot and no domain-level enrichment data support PM1.

The gene-level PVS1 review does not provide robust evidence that PDGFRA disease is primarily caused by truncating variants; BP1 is not met. PVS1 is not applicable to this missense variant.

PM2 (supporting pathogenic) and BP4 (supporting benign) are both met; the evidence is balanced and does not reach a classification threshold in either direction.

Using the generic ACMG/AMP 2015 combination rules (Richards et al., PMID:25741868), one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) result in 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	Missense variant (p.Ala663Val); does not fall into PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice site). PVS1 framework is not applicable to missense variants.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No other nucleotide change at this position (p.Ala663) has been reported as pathogenic. This variant is absent from ClinVar; no comparator nucleotide change producing the same amino acid change exists to support PS1.	clinvar
PS2	Not met	No de novo evidence (with confirmed paternity/maternity) is available for this variant. No publications or case reports document this variant occurring as a de novo event.
PS3	Not met	No well-established in vitro or in vivo functional studies supporting a damaging effect have been identified for this variant. OncoKB classifies this variant as Unknown Oncogenic Effect and reports no variant-specific functional evidence. No publications with functional data for p.Ala663Val were found.	oncokb
PS4	Not met	No case-control or cohort data demonstrate significantly increased prevalence of this variant in affected individuals compared to controls. The variant is absent from ClinVar and COSMIC; no patient-based statistical evidence is available.	clinvar
PS5	Not met	No reputable source (e.g., ClinVar expert panel) has classified this variant as pathogenic. The variant is absent from ClinVar entirely.	clinvar
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot (cancerhotspots.org). While residue A663 is located in the PDGFRA tyrosine kinase domain, no domain-level evidence establishes that missense variants in this specific region are enriched among pathogenic variants. COSMIC reports no entries at this residue.
PM2	Met	This variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (0/1,607,834 alleles), meeting the allele frequency threshold for PM2 supporting (<0.1% in population databases).	gnomad_v2 gnomad_v4
PM5	Not met	No different missense change at codon 663 has been reported as pathogenic. PM5 candidate analysis found zero same-residue candidates in ClinVar.	pm5_candidates clinvar
PM6	Not met	No de novo occurrence data (without confirmation of paternity/maternity) are available for this variant.
PP1	Not met	No co-segregation data are available for this variant. No family-based linkage or segregation studies have been reported.
PP2	Not met	No gene-level constraint metrics (z-score, missense constraint) are available for PDGFRA in the evidence set. HCI prior probability was not calculable for this gene. PP2 cannot be applied without demonstrated low rate of benign missense variation.
PP3	Not met	In silico evidence is conflicting. REVEL score is 0.755 (damaging), but BayesDel score is 0.21064 (benign) and SpliceAI predicts no splicing impact (max delta 0.00). Multiple lines of computational evidence do not converge on a deleterious effect; only one tool (REVEL) supports pathogenicity.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history information is available to assess phenotype specificity. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology.
PP5	Not met	This variant is absent from ClinVar. No reputable source, expert panel, or clinical laboratory has classified this variant as pathogenic or likely pathogenic.	clinvar
BA1	Not met	This variant is absent from gnomAD (0/1,607,834 alleles in v4.1). Allele frequency is 0.00%, far below the BA1 threshold of >1%.	gnomad_v4
BS1	Not met	This variant is absent from gnomAD (0/1,607,834 alleles in v4.1). Allele frequency is 0.00%, far below the BS1 threshold of >0.3%.	gnomad_v4
BS2	Not met	No data on observation in healthy adults are available. BS2 requires the variant to be observed in a healthy adult individual for a recessive, or in trans with a pathogenic variant for a dominant, disorder with full penetrance expected at an early age.
BS3	Not met	No well-established in vitro or in vivo functional studies show no deleterious effect for this variant. No functional studies of any kind were identified for p.Ala663Val.
BS4	Not met	No segregation data are available for this variant. BS4 requires lack of segregation with disease in affected family members.
BP1	Not met	The gene-level PVS1 context review identified papers mentioning PDGFRA, but these papers do not establish that PDGFRA disease is primarily caused by truncating variants. The supporting publications discuss SDH-deficient GISTs that are KIT/PDGFRA mutation-negative, or describe SDHA germline variants with incidental somatic PDGFRA driver mutations — they do not demonstrate PDGFRA loss-of-function as a primary germline disease mechanism. BP1 requires robust evidence that the gene causes disease primarily through truncating variants; this evidence is absent.	pvs1_gene_context
BP2	Not met	No data on observation in trans with a pathogenic variant are available.
BP4	Met	Multiple lines of computational evidence suggest no impact on gene product. BayesDel predicts a benign score (0.21064, below the 0.3 threshold). SpliceAI predicts no splicing impact (max delta score = 0.00). Two independent in silico tools converge on a neutral/benign prediction.	bayesdel spliceai
BP5	Not met	No evidence of an alternate molecular basis for disease in a case harboring this variant is available.
BP6	Not met	This variant is absent from ClinVar. No reputable source has classified this variant as benign or likely benign.	clinvar
BP7	N/A	This is a missense variant (p.Ala663Val), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	In-frame deletion/insertion criterion; variant is a single-nucleotide substitution (missense), not an in-frame indel.
PM3	N/A	Skipped per case instructions; not assessed.
PM4	N/A	Skipped per case instructions; variant is a substitution, not a protein-length-altering change.

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