NM_001982.4:c.994G>A (p.Glu332Lys) is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population databases (PM2).1 The variant affects ERBB3 residue Glu332, a statistically significant single-residue hotspot (cancerhotspots.org Q-value 4.75e-7) confirmed by OncoKB, satisfying PM1.2 In silico predictors REVEL (0.614) and BayesDel (0.108) favor a deleterious missense effect while SpliceAI predicts no splicing impact, supporting PP3.3 Germline ERBB3 disease is associated with biallelic loss-of-function variants; missense variants are not an established germline disease mechanism, supporting BP1.4 No germline functional, segregation, de novo, case-control, or ClinVar evidence is available; the combined evidence (PM1 + PM2 + PP3 versus BP1) is insufficient for a likely pathogenic or likely benign call, and the variant is classified as a Variant of Uncertain Significance (VUS).5
ERBB3
Final classification
VUS
PM1PM2PP3BP1
ERBB3
c.994G>A
p.Glu332Lys
missense
This variant
NM_001982.4:c.994G>A (p.Glu332Lys) is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada 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: PM1 moderate, PM2 supporting, PP3 supporting, BP1 supporting benign; combination = 1 moderate + 2 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM1PM2PP3
BP1
VUS
ERBB3 c.994G>A
missense
PM1 + PM2 + PP3 + BP1
→
VUS
Gene diagram
· NM_001982.4 · variants mapped to exon structure
ERBB3
NM_001982.4
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 19 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
moderate
Pathogenic
The variant alters ERBB3 residue Glu332, a statistically significant single-residue hotspot (cancerhotspots.org, Q-value 4.75e-7; Chang et al. 2017) confirmed by OncoKB as a statistically significant hotspot, satisfying PM1.
cancerhotspots.org: ERBB3 E332 single-residue hotspotQ-value 4.75e-7 (Chang et al. 2017)OncoKB confirms 'identified as a statistically significant hotspot'
✓
PM2
supporting
Pathogenic
The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population databases, meeting PM2 (allele frequency < 0.1%).
Absent from gnomAD v2.1 (exome)gnomAD v4.1 (exome)and gnomAD-Canada v1.0 (genomes).
✓
PP3
supporting
review
Pathogenic
In silico tools favor a deleterious effect (REVEL 0.614; BayesDel 0.108), while SpliceAI predicts no splicing impact (max delta 0.01); PP3 is met at supporting strength.
REVEL 0.614 (damaging-leaning)BayesDel noAF 0.108SpliceAI max delta 0.008 (no splice impact).
✓
BP1
supporting
review
Benign
Germline ERBB3 disease is associated with biallelic loss-of-function variants; missense variants are not an established germline disease mechanism, so BP1 (missense variant in a gene where primarily truncating variants cause disease) applies at supporting benign strength.
Germline ERBB3 disease = biallelic loss-of-function multisystem syndrome (PMID 31752936)missense is not the established germline mechanism.
Assessed · not applied
· 19 not met · 0 not assessed
Pathogenic
PS1
No previously established pathogenic variant with the same amino acid change (p.Glu332Lys) was identified; the variant is absent from ClinVar.
PS2
No de novo occurrence with confirmed parentage has been reported for this variant.
PS3
No variant-specific functional data exist; OncoKB explicitly states no functional data are available for ERBB3 E332K, and no functional study was identified in the reviewed literature.
PS4
No case-control or affected-cohort prevalence data are available to assess enrichment of this variant in affected individuals.
PM5
No different pathogenic missense variant at the same residue (Glu332) was identified to serve as a comparator; PM5 is not met.
PM6
No de novo observation (without confirmed parentage) has been reported for this variant.
PP1
No cosegregation data with disease in affected family members are available.
PP2
Missense is not an established germline disease mechanism for ERBB3 (germline disease is biallelic loss-of-function), and there is no evidence of a low benign missense rate in this gene.
PP4
No patient phenotype or family history specific to an ERBB3-related disorder was available for assessment.
PP5
No reputable source (e.g., ClinVar expert panel) reports this variant as pathogenic; the variant is absent from ClinVar.
Benign
BA1
The variant is absent from population databases, far below the BA1 (>1%) allele frequency threshold.
BS1
The variant is absent from population databases, below the BS1 (>0.3%) allele frequency threshold.
BS2
The variant has not been observed in healthy adults; it is absent from gnomAD, so BS2 is not met.
BS3
No well-established functional studies demonstrating a benign (non-deleterious) effect exist; no functional data are available for this variant.
BS4
No segregation data demonstrating absence of cosegregation with disease are available.
BP2
No observation of this variant in trans with a pathogenic variant (or cis with a pathogenic variant in a recessive disorder) is available.
BP4
In silico predictors do not support a benign effect (REVEL 0.614 and BayesDel 0.108 favor deleterious); BP4 is not met.
BP5
No case in which the variant co-occurs with an alternate molecular basis for disease was identified.
BP6
No reputable source reports this variant as benign; the variant is absent from ClinVar.
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
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 = 0.01). REVEL score = 0.614. BayesDel score = 0.107745.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57246601, n = 39 times).
Hotspots
This variant lies in a statistically significant hotspot.
Sources & reference links