NM_006206.5:c.1780G>A (p.Val594Met) in PDGFRA is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).1 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.2 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.3 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.4 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.5
PDGFRA
Final classification
VUS
PDGFRA c.1780G>A · p.Val594Met
PDGFRA
NM_006206.5:c.1780G>A (p.Val594Met) in PDGFRA is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).
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.
Classification rationale
PM2
VUS
PDGFRA c.1780G>A
PM2
→
VUS
3
revelbayesdelspliceai ↗
4
pm5_candidatesoncokb ↗
Gene diagram
· NM_006206.5 · variants mapped to exon structure
PDGFRA
NM_006206.5
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 22 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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).
Absent from gnomAD v2.1 (exomes)absent from gnomAD v4.1 (exomes)absent from gnomAD-Canada v1.0.
Assessed · not applied
Pathogenic
PS1
No alternative nucleotide change at codon 594 resulting in the same amino acid substitution (Val594Met) has been established as pathogenic.
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.
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.
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.
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.
PM5
No pathogenic missense variant at the same residue (Val594) with a different amino acid change has been identified.
PM6
No assumed de novo occurrence of NM_006206.5:c.1780G>A has been reported (without confirmation of paternity and maternity).
PP1
No cosegregation data for NM_006206.5:c.1780G>A with PDGFRA-associated disease in multiple affected family members has been reported.
PP2
HCI prior data is unavailable for PDGFRA (gene not supported), precluding confirmation of a low rate of benign missense variation.
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).
PP4
No patient phenotype or family history data specific to a disease with a single genetic etiology are available for this variant.
PP5
ClinVar reports NM_006206.5:c.1780G>A as Uncertain significance (criteria provided, single submitter) from two clinical laboratories.
Benign
BA1
NM_006206.5:c.1780G>A is absent from gnomAD v2.1 and v4.1.
BS1
NM_006206.5:c.1780G>A is absent from gnomAD v2.1 and v4.1.
BS2
NM_006206.5:c.1780G>A is absent from gnomAD population databases.
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.
BS4
No segregation data are available for NM_006206.5:c.1780G>A to demonstrate lack of cosegregation with disease in affected family members.
BP1
PDGFRA-associated disease (e.g., GIST) is primarily driven by gain-of-function missense variants rather than exclusively by truncating variants.
BP2
No evidence that NM_006206.5:c.1780G>A has been observed in cis or in trans with a pathogenic PDGFRA variant.
BP4
Computational evidence is conflicting.
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.
BP6
ClinVar reports NM_006206.5:c.1780G>A as Uncertain significance, not benign.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 4 PMIDs not cited in assessment
23852704 ↗
Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update.
CLINVAR
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.
CLINVAR
22685257 ↗
The UK NEQAS for Molecular Genetics scheme for gastrointestinal stromal tumour: findings and recommendations following four rounds of circulation.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR