NM_002067.5:c.892C>T

GNA11 · NP_002058.2:p.(Pro298Ser) · NM_002067.5

GRCh37: chr19:3120989 C>T · GRCh38: chr19:3120991 C>T

Gene: GNA11 Transcript: NM_002067.5

Final call

VUS

PM2 moderate

Variant details

Gene

GNA11

Transcript

NM_002067.5

Protein

NP_002058.2:p.(Pro298Ser)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002067.5:c.892C>T (p.Pro298Ser) in GNA11 is a missense variant absent from gnomAD population databases (PM2).

The variant has been observed in COSMIC (COSV50138421, n=3) in somatic cancers but is absent from ClinVar with no germline classification available.

In silico predictors are conflicting: REVEL score 0.535 is borderline damaging while BayesDel score -0.247 is benign; SpliceAI predicts no splicing impact (max delta 0.00). Neither PP3 nor BP4 is met.

No functional studies, segregation data, de novo reports, or phenotype-specific evidence were identified for this variant.

With only PM2 (moderate) met and no supporting pathogenic or benign criteria, the variant does not meet any ACMG/AMP classification combination and defaults to Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 rules.

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.Pro298Ser); does not fall into PVS1 null-variant buckets (nonsense, frameshift, canonical ±1,2 splice consensus). The ClinGen SVI PVS1 framework (PMC6185798) does not apply to missense substitutions.	pvs1_generic_framework
PS1	Not met	No previously established pathogenic variant at amino acid position 298 has been identified. The variant is absent from ClinVar and no same-residue comparator with an established pathogenic classification was found.	clinvar pm5_candidates
PS2	Not met	No de novo data available for this variant. No publications with de novo confirmation of NM_002067.5:c.892C>T were identified.
PS3	Not met	No variant-specific functional studies identified. OncoKB reports Unknown Oncogenic Effect for P298S. No publications with experimental functional data for NM_002067.5:c.892C>T were found in the case materials.	oncokb
PS4	Not met	No case-control or prevalence data available. The variant has been observed in COSMIC (somatic, n=3) but no germline case data with statistical comparison to controls was identified.
PS5	Not met	No alternate source has classified this variant as pathogenic. The variant is absent from ClinVar and no diagnostic laboratory classification was found.	clinvar
PM1	Not met	Position 298 is not a statistically significant mutational hotspot per cancerhotspots.org. No domain-level functional evidence specific to the Pro298 residue was identified in the case materials. GNA11 has well-characterized gain-of-function hotspots at R183 and Q209, but P298 is not among the established critical residues.
PM2	Met	NM_002067.5:c.892C>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (allele frequency = 0%). Meets PM2 threshold (<0.1% in population databases) under generic ACMG/AMP 2015 criteria.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue pathogenic comparator variant identified. PM5 candidate harvesting returned no candidates at Pro298 with an established pathogenic classification.	pm5_candidates
PM6	Not met	No de novo data available for NM_002067.5:c.892C>T. No publications reporting de novo occurrence were identified.
PP1	Not met	No co-segregation data available. No family studies or pedigrees with this variant were identified.
PP2	Not assessed	HCI prior data not available for GNA11 (gene not supported by the predictor). Missense constraint (z-score) cannot be assessed without this metric. Gene-level missense tolerance data is unavailable in the case materials.
PP3	Not met	In silico predictors are conflicting: REVEL 0.535 (borderline damaging, just above 0.5 threshold), BayesDel -0.247 (benign), SpliceAI max delta 0.00 (no splicing impact). Multiple lines of computational evidence do not consistently support a deleterious effect; the conflicting data does not satisfy PP3 requirements.	revel bayesdel spliceai
PP4	Not met	No patient phenotype data available to assess whether the clinical presentation is specific for a GNA11-related disorder. No case-level phenotypic information was provided.
PP5	Not met	Absent from ClinVar. No 3-star expert panel or other reputable source has classified NM_002067.5:c.892C>T as pathogenic. PP5 default supporting strength cannot be applied without a ClinVar entry meeting the review status threshold.	clinvar
BA1	Not met	Allele frequency is 0% in gnomAD (v2.1, v4.1, Canada), well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Allele frequency is 0% in gnomAD, below the BS1 threshold of >0.3% for non-VCEP assessment.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Variant is absent from population databases; cannot confirm observation in healthy adults. No case-level data showing co-occurrence with another pathogenic variant or presence in an unaffected individual was identified.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating no deleterious effect were identified. OncoKB reports Unknown Oncogenic Effect. No publications with experimental data showing benign functional impact for this variant were found.	oncokb
BS4	Not met	No segregation data available. No family studies showing lack of segregation with disease were identified.
BP1	Not met	GNA11 has established gain-of-function missense mutations (e.g., Q209, R183) causing constitutive activation in somatic disease and missense variants associated with germline vascular malformations. It cannot be concluded that only truncating variants cause GNA11-related disease; missense variants are a recognized disease mechanism.	pvs1_gene_context
BP2	Not met	No data on trans configuration with a known pathogenic variant. No case-level genotyping data was available to assess allelic phase.
BP4	Not met	In silico evidence is conflicting: REVEL 0.535 is borderline damaging (>0.5 threshold), while BayesDel -0.247 is confidently benign (<0). Multiple lines of computational evidence do not consistently suggest no impact on the gene product, so BP4 is not met.	revel bayesdel spliceai
BP5	Not met	No alternate molecular basis identified. No case-level data showing a different causal variant in the proband was available.
BP6	Not met	Absent from ClinVar. No 3-star expert panel or other reputable source has classified NM_002067.5:c.892C>T as benign. BP6 default supporting benign strength cannot be applied without a ClinVar entry.	clinvar
BP7	N/A	Missense variant; BP7 is reserved for synonymous variants with no predicted splicing impact. NM_002067.5:c.892C>T is a missense substitution (p.Pro298Ser).

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