NM_006206.5:c.1780G>A

PDGFRA · NP_006197.1:p.(Val594Met) · NM_006206.5

GRCh37: chr4:55141134 G>A · GRCh38: chr4:54274967 G>A

Gene: PDGFRA Transcript: NM_006206.5

Final call

VUS

PM2 supporting

Variant details

Gene

PDGFRA

Transcript

NM_006206.5

Protein

NP_006197.1:p.(Val594Met)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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	NM_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).	pvs1_generic_framework
PS1	Not met	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.	pm5_candidates
PS2	Not met	No de novo occurrence of NM_006206.5:c.1780G>A with confirmed paternity and maternity has been reported in the literature or databases.
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrating a damaging effect on PDGFRA protein function have been identified for p.Val594Met.
PS4	Not met	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.	gnomad_v2 gnomad_v4 clinvar
PS5	Not met	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).	pm5_candidates
PM1	Not met	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.
PM2	Met	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).	gnomad_v2 gnomad_v4
PM5	Not met	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.	pm5_candidates
PM6	Not met	No assumed de novo occurrence of NM_006206.5:c.1780G>A has been reported (without confirmation of paternity and maternity).
PP1	Not met	No cosegregation data for NM_006206.5:c.1780G>A with PDGFRA-associated disease in multiple affected family members has been reported.
PP2	Not met	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not met	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.
PP5	Not met	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.	clinvar
BA1	Not met	NM_006206.5:c.1780G>A is absent from gnomAD v2.1 and v4.1. BA1 requires an allele frequency >1% in any population.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not met	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.
BS4	Not met	No segregation data are available for NM_006206.5:c.1780G>A to demonstrate lack of cosegregation with disease in affected family members.
BP1	Not met	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.
BP2	Not met	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.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not met	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.
BP6	Not met	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.	clinvar
BP7	N/A	NM_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.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions. This variant is a single nucleotide substitution.
PM3	N/A	PM3 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.
PM4	N/A	PM4 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.

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