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

PDGFRA

Transcript

NM_006206.5

HGVS · transcript:coding

NM_006206.5:c.1780G>A

Consequence

N/A

GRCh38

chr4:54274967 G>A

GRCh37

chr4:55141134 G>A

Basis 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. ▾

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

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

PM2 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 clinvar ↗

3 revelbayesdelspliceai ↗

4 pm5_candidatesoncokb ↗

5 pvs1_generic_framework ↗

Gene diagram · NM_006206.5 · variants mapped to exon structure

PDGFRA NM_006206.5

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

Population frequency

“

Absent from gnomAD v4.1.

“

Absent from gnomAD v2.1.

“

This variant is absent from gnomAD-Canada.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 1519216)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.55. BayesDel score = 0.0893606.

SpliceAI ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Literature · 4 PMIDs triaged · 2 high-priority

4papers screened

Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.

23852704 ↗ functional

Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update.

Biomarkers currently play an important role in the detection and management of patients with several different types of gastrointestinal cancer, especially colorectal, gastric, gastro-oesophageal junction (GOJ) adenocarcinomas and gastrointestinal stromal tumors (GISTs). The aim of this article is to provide updated and evidence-based guidelines for the use of biomarkers in the different gastroint

BS3PP5PS3PS4

25394175 ↗ case observation

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.

The practice guidelines of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) are developed by members of the ACMG and NSGC to assist medical geneticists, genetic counselors, and other health-care providers in making decisions about appropriate management of genetic concerns, including access to and/or delivery of services. Each pract

PP5PS4

22685257 ↗ background review

The UK NEQAS for Molecular Genetics scheme for gastrointestinal stromal tumour: findings and recommendations following four rounds of circulation.

PP5PS4

28492532 ↗ background review

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

PP5PS4

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots