Variant classification summary

NM_002072.5:c.626A>C

GNAQ · NP_002063.2:p.(Gln209Pro) · NM_002072.5

GRCh37: chr9:80409488 T>G · GRCh38: chr9:77794572 T>G

Gene: GNAQ Transcript: NM_002072.5

Final call

Likely Pathogenic

PS3 supporting PM1 moderate PM2 supporting PP3 strong

Variant details

Gene

GNAQ

Transcript

NM_002072.5

Protein

NP_002063.2:p.(Gln209Pro)

gnomAD AF

ClinVar

Tier I - Strong

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: Q209P showed diminished GTPase activity and oncogenic downstream signaling.

2

PM1 moderate: codon 209 is a recurrent statistically significant GNAQ hotspot.

3

PM2 supporting: the variant is absent from all reported gnomAD datasets.

4

PP3 strong: REVEL 0.956 exceeds the 0.932 strong threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong, one moderate, and two supporting pathogenic criteria support a Likely Pathogenic call.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no prior established pathogenic variant with the same GNAQ p.Gln209Pro amino-acid change was documented.	clinvar PMID:35804836
PS2	Not assessed	Not assessed: no qualifying case-specific de novo report confirms both maternity and paternity or documents absence of family history.
PS3	Met	Met at supporting strength: purified Q209P showed diminished GTPase activity, and cell assays showed downstream signaling comparable to oncogenic Q209L.	PMID:30352874 PMID:35804836
PS4	Not met	Not met: available studies report affected tumor cohorts, not unaffected or population controls, so no valid PS4 odds ratio or confidence interval exceeds 5.0 with its interval excluding 1.0.	PMID:29891723 PMID:21487925
PM1	Met	Met, moderate: GNAQ codon 209 is a statistically significant recurrent hotspot, with mutations reported exclusively at this codon in the cited cohort.	hotspots PMID:19078957 PMID:35804836
PM2	Met	Met at supporting strength: the variant was absent from every reported gnomAD dataset, corresponding to AF 0 versus the PM2 threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no pathogenic partner variant or parental/offspring testing establishes that GNAQ p.Gln209Pro is in trans in an affected proband.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: GNAQ p.Gln209Leu is a same-residue comparator, but its pathogenic status is not established by the available evidence.	PMID:19078957
PM6	Not assessed	Not assessed: no case-specific report establishes an assumed de novo occurrence of this variant in an affected patient.
PP1	Not assessed	Not assessed: no affected relatives, genotyped family members, or informative cosegregation data are reported.
PP2	Not assessed	Not assessed: GNAQ has a documented missense mechanism, but its low rate of benign missense variation is not established.	PMID:19078957 PMID:35804836
PP3	Met	Met, strong: REVEL 0.956 exceeds the generic PP3 strong threshold of 0.932 for missense variants.	revel
PP4	Not assessed	Not assessed: the patient's phenotype, family history, and a single-genetic-etiology diagnosis are not provided for evaluating PP4.
PP5	Not met	Not met: ClinVar has zero expert-panel submissions and only a single-submitter somatic oncology record, not an exact-variant expert-panel Pathogenic or Likely pathogenic classification.	clinvar PMID:21487925 PMID:29891723 oncokb
BA1	Not met	Not met: the variant was absent from all reported gnomAD datasets, so no grpmax FAF reaches the BA1 threshold of >=0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: all reported gnomAD datasets were absent, providing no grpmax FAF at or above the generic BS1 default of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no documented healthy adult germline carrier and no established full-penetrance early-onset disorder context are available.
BS3	Not assessed	Not assessed: no well-established assay in the reviewed evidence demonstrated that GNAQ p.Gln209Pro has no damaging effect.	PMID:30352874 PMID:35804836
BS4	Not assessed	Not assessed: no affected relatives with negative variant testing are reported to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: available evidence favors recurrent activating missense disease biology, but a comprehensive truncating-versus-missense disease spectrum is unavailable.	PMID:19078957 PMID:35804836
BP2	Not assessed	Not assessed: no phase-tested affected proband shows GNAQ p.Gln209Pro with a pathogenic variant in cis or in trans.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.956 is above the generic BP4 supporting threshold of 0.29 for missense variants.	revel
BP5	Not assessed	Not assessed: no case-level evidence shows this exact variant alongside an alternate molecular basis that explains the patient's disease.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present, and the sole submitter is a somatic oncology laboratory.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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