NM_002067.5:c.892C>T (p.Pro298Ser) in GNA11 is a missense variant absent from gnomAD population databases (PM2).1 The variant has been observed in COSMIC (COSV50138421, n=3) in somatic cancers but is absent from ClinVar with no germline classification available.2 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.3 No functional studies, segregation data, de novo reports, or phenotype-specific evidence were identified for this variant.4 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.5
GNA11
Final classification
VUS
GNA11 c.892C>T · p.Pro298Ser
GNA11
NM_002067.5:c.892C>T (p.Pro298Ser) in GNA11 is a missense variant absent from gnomAD population databases (PM2).
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 moderate; combination = 1 moderate, which maps to VUS.
Classification rationale
PM2
VUS
GNA11 c.892C>T
PM2
→
VUS
Gene diagram
· NM_002067.5 · variants mapped to exon structure
GNA11
NM_002067.5
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 21 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
Pathogenic
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.
Absent from gnomAD v2.1 (AC=0).Absent from gnomAD v4.1 (AC=0).Absent from gnomAD-Canada v1.0 (AC=0).
Assessed · not applied
Pathogenic
PS1
No previously established pathogenic variant at amino acid position 298 has been identified.
PS2
No de novo data available for this variant.
PS3
No variant-specific functional studies identified.
PS4
No case-control or prevalence data available.
PM1
Position 298 is not a statistically significant mutational hotspot per cancerhotspots.org.
PM6
No de novo data available for NM_002067.5:c.892C>T.
PP1
No co-segregation data available.
PP2
HCI prior data not available for GNA11 (gene not supported by the predictor).
PP3
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).
PP4
No patient phenotype data available to assess whether the clinical presentation is specific for a GNA11-related disorder.
PP5
Absent from ClinVar.
Benign
BA1
Allele frequency is 0% in gnomAD (v2.1, v4.1, Canada), well below the BA1 threshold of >1%.
BS1
Allele frequency is 0% in gnomAD, below the BS1 threshold of >0.3% for non-VCEP assessment.
BS2
Variant is absent from population databases; cannot confirm observation in healthy adults.
BS3
No functional studies demonstrating no deleterious effect were identified.
BS4
No segregation data available.
BP1
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.
BP2
No data on trans configuration with a known pathogenic variant.
BP4
In silico evidence is conflicting: REVEL 0.535 is borderline damaging (>0.5 threshold), while BayesDel -0.247 is confidently benign (<0).
BP5
No alternate molecular basis identified.
BP6
Absent from ClinVar.
N/A · 3
PVS1 · PM5 · 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
Absent from gnomAD-Canada v1.0.
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.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.535. BayesDel score = -0.246968.
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. GNA11, a G protein subunit, is recurrently mutated in uveal melanoma.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV50138421, n = 3 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links