NM_001982.4: c.994G>A

ERBB3 · NP_001973.2:p.(Glu332Lys) · NM_001982.4

GRCh37: chr12:56482537 G>A · GRCh38: chr12:56088753 G>A

Gene: ERBB3 Transcript: NM_001982.4

Final call

VUS

PM1 moderate PM2 supporting PP3 supporting BP1 supporting benign

Variant details

Gene

ERBB3

Transcript

NM_001982.4

Protein

NP_001973.2:p.(Glu332Lys)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001982.4:c.994G>A (p.Glu332Lys) is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population databases (PM2).

The variant affects ERBB3 residue Glu332, a statistically significant single-residue hotspot (cancerhotspots.org Q-value 4.75e-7) confirmed by OncoKB, satisfying PM1.

In silico predictors REVEL (0.614) and BayesDel (0.108) favor a deleterious missense effect while SpliceAI predicts no splicing impact, supporting PP3.

Germline ERBB3 disease is associated with biallelic loss-of-function variants; missense variants are not an established germline disease mechanism, supporting BP1.

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).

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	NM_001982.4:c.994G>A is a missense substitution (p.Glu332Lys), not a null variant; PVS1 applies only to loss-of-function variants (nonsense, frameshift, canonical +/-1,2 splice, or initiation codon), so this criterion is not applicable.	pvs1_variant_assessment
PS1	Not met	No previously established pathogenic variant with the same amino acid change (p.Glu332Lys) was identified; the variant is absent from ClinVar.	clinvar
PS2	Not met	No de novo occurrence with confirmed parentage has been reported for this variant.
PS3	Not met	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.	oncokb
PS4	Not met	No case-control or affected-cohort prevalence data are available to assess enrichment of this variant in affected individuals.
PS5	Not met	No evidence satisfies PS5; no established pathogenic attribution or equivalent source for this variant was identified.
PM1	Met	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.	oncokb
PM2	Met	The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population databases, meeting PM2 (allele frequency < 0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No different pathogenic missense variant at the same residue (Glu332) was identified to serve as a comparator; PM5 is not met.	pm5_candidates
PM6	Not met	No de novo observation (without confirmed parentage) has been reported for this variant.
PP1	Not met	No cosegregation data with disease in affected family members are available.
PP2	Not met	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.	pvs1_gene_context
PP3	Met	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 bayesdel spliceai
PP4	Not met	No patient phenotype or family history specific to an ERBB3-related disorder was available for assessment.
PP5	Not met	No reputable source (e.g., ClinVar expert panel) reports this variant as pathogenic; the variant is absent from ClinVar.	clinvar
BA1	Not met	The variant is absent from population databases, far below the BA1 (>1%) allele frequency threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from population databases, below the BS1 (>0.3%) allele frequency threshold.	gnomad_v2 gnomad_v4
BS2	Not met	The variant has not been observed in healthy adults; it is absent from gnomAD, so BS2 is not met.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrating a benign (non-deleterious) effect exist; no functional data are available for this variant.	oncokb
BS4	Not met	No segregation data demonstrating absence of cosegregation with disease are available.
BP1	Met	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.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a pathogenic variant (or cis with a pathogenic variant in a recessive disorder) is available.
BP4	Not met	In silico predictors do not support a benign effect (REVEL 0.614 and BayesDel 0.108 favor deleterious); BP4 is not met.	revel bayesdel spliceai
BP5	Not met	No case in which the variant co-occurs with an alternate molecular basis for disease was identified.
BP6	Not met	No reputable source reports this variant as benign; the variant is absent from ClinVar.	clinvar
BP7	N/A	This is a missense variant (p.Glu332Lys), not a synonymous variant; BP7 is not applicable.
BP3	N/A	Missense substitution, not an in-frame deletion/insertion in a repetitive region.
PM3	N/A	No recessive disorder with a pathogenic variant in trans was identified for this variant.
PM4	N/A	Missense substitution, not a protein-length-altering in-frame indel or stop-loss variant.

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