NM_001982.3:c.244G>A

ERBB3 · NP_001973.2:p.(Glu82Lys) · NM_001982.3

GRCh37: chr12:56478788 G>A · GRCh38: chr12:56085004 G>A

Gene: ERBB3 Transcript: NM_001982.3

Final call

VUS

PM2 moderate PP3 supporting

Variant details

Gene

ERBB3

Transcript

NM_001982.3

Protein

NP_001973.2:p.(Glu82Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001982.3:c.244G>A (p.Glu82Lys) is a missense variant in ERBB3 exon 3.

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (0 alleles across all populations), meeting PM2 at moderate strength.

Multiple in silico predictors support a deleterious effect: REVEL score 0.948 (strongly pathogenic) and BayesDel score 0.443 (intermediate, leaning deleterious), meeting PP3 at supporting strength.

PVS1 is not applicable as c.244G>A is a missense variant, not a null variant (nonsense, frameshift, or canonical ±1,2 splice). Per ClinGen SVI PVS1 recommendations (PMC6185798), the generic PVS1 framework applies only to predicted null variants.

The variant is absent from ClinVar, absent from COSMIC, and not located in a statistically significant mutational hotspot (CancerHotspots). No literature PMIDs were identified for this variant. OncoKB classifies it as 'Unknown Oncogenic Effect' without variant-specific functional evidence.

No de novo, segregation, case-control, functional, or phenotype-specific data are available for this variant; PS2, PS3, PS4, PP1, PP4, PM6, and benign criteria BS2-BS4, BP5-BP6 remain not assessed.

PM5 is not applicable as no pathogenic missense comparator at ERBB3 residue E82 was identified. BP7 is not applicable to missense variants.

Overall classification: 1 moderate pathogenic criterion (PM2) and 1 supporting pathogenic criterion (PP3) are met. Under the generic ACMG/AMP 2015 combination rules (PMID:25741868), this does not reach the Likely Pathogenic threshold (minimum: 3 moderate, or 2 moderate + 2 supporting, or 1 moderate + 4 supporting). 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_001982.3:c.244G>A is a missense variant (p.Glu82Lys), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). Per the ClinGen SVI PVS1 decision tree (PMC6185798), generic PVS1 framework applies only to null variants. This missense substitution falls into the 'other' bucket and is ineligible for PVS1 adjudication.	pvs1_generic_framework pvs1_variant_assessment pvs1_gene_context
PS1	Not assessed	PS1 requires a different nucleotide change resulting in the same amino acid substitution (E82K) previously established as pathogenic. No such variant is present in ClinVar and no literature PMIDs were identified for this case. Without an established pathogenic comparator at residue 82, PS1 cannot be assessed.	clinvar
PS2	Not assessed	PS2 requires a confirmed de novo occurrence with parental confirmation. No de novo data, family studies, or trio sequencing reports are available for this variant.
PS3	Not assessed	PS3 requires well-established functional studies demonstrating a deleterious effect. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. No literature PMIDs with functional data were identified.	oncokb
PS4	Not assessed	PS4 requires a statistically significant enrichment in affected individuals versus controls. No case-control or cohort prevalence data are available. The variant is absent from ClinVar and COSMIC, precluding any case-count analysis.	clinvar gnomad_v2 gnomad_v4 gnomad_canada
PS5	Not assessed	PS5 requires a reputable source (e.g., expert panel, clinical laboratory) to have recently reported this variant as pathogenic with evidence not independently available. The variant is absent from ClinVar entirely; no reputable source has classified it.	clinvar
PM1	Not met	PM1 requires the variant to be located in a mutational hotspot or well-established critical functional domain without benign variation. Residue E82 lies within the extracellular domain of ERBB3 (exon 3). CancerHotspots does not identify this position as statistically significant. No ClinGen- or VCEP-defined critical domain with pathogenic missense enrichment has been established for ERBB3.
PM2	Met	NM_001982.3:c.244G>A is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada. Complete absence from large population databases (allele frequency 0%, well below the 0.1% threshold for PM2) constitutes moderate evidence of pathogenicity under the ACMG/AMP 2015 framework.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 requires a different pathogenic missense change at the same amino acid residue (E82). Automated and targeted ClinVar candidate harvesting identified zero same-residue pathogenic missense comparators at ERBB3 residue 82. PM5 cannot be applied without a qualifying comparator.	pm5_candidates
PM6	Not assessed	PM6 requires a confirmed de novo occurrence without parental confirmation, or a de novo assumption. No de novo data are available for this variant.
PP1	Not assessed	PP1 requires co-segregation of the variant with disease in multiple affected family members. No family or segregation data are available.
PP2	Not assessed	PP2 requires the gene to have a low rate of benign missense variation and for missense variants to be a common disease mechanism. HCI Prior data are unavailable for ERBB3 (gene not supported), precluding quantitative assessment of missense constraint. While ERBB3 LOF is supported as a germline disease mechanism, the relative contribution of missense vs. truncating variants cannot be determined without constraint metrics.
PP3	Met	Multiple in silico predictors support a deleterious effect. REVEL score of 0.948 (strongly pathogenic) and BayesDel score of 0.443 (intermediate, leaning deleterious). SpliceAI predicts no splice impact (max delta 0.00), which is expected for an exonic missense. The convergence of REVEL and BayesDel toward a damaging prediction meets PP3 at supporting strength.	revel bayesdel spliceai
PP4	Not assessed	PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. No patient phenotype information is available for this case.
PP5	Not assessed	PP5 requires a reputable source (e.g., expert panel, clinical laboratory) to have recently classified this variant as pathogenic. The variant is absent from ClinVar and no expert panel classification exists.	clinvar
BA1	Not met	BA1 requires allele frequency > 1% in population databases. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0%). Does not meet the BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	BS1 requires allele frequency greater than expected for the disorder (> 0.3% by non-VCEP criteria). The variant is absent from all gnomAD datasets (allele frequency 0%). Does not meet the BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	BS2 requires observation of the variant in a healthy adult for a fully penetrant dominant disorder, or observation in trans with a pathogenic variant for a recessive disorder. No phenotypic data on healthy carriers are available.
BS3	Not assessed	BS3 requires well-established functional studies demonstrating no deleterious effect. No functional studies were identified for this variant (OncoKB: Unknown Oncogenic Effect; zero literature PMIDs).	oncokb
BS4	Not assessed	BS4 requires lack of segregation of the variant with disease in affected family members. No family studies or segregation data are available.
BP1	Not met	BP1 requires a missense variant in a gene for which primarily truncating variants are known to cause disease. While biallelic ERBB3 loss-of-function variants are associated with a multisystem syndrome (PMID:31752936), the literature also supports missense variants as potentially contributory to ERBB3-related phenotypes. The disease mechanism is not exclusively limited to truncating variants, so BP1 cannot be applied.	pvs1_gene_context
BP2	Not assessed	BP2 requires observation of the variant in trans with a pathogenic variant in a fully penetrant recessive disorder, or in cis with a pathogenic variant. No such data are available.
BP4	Not met	BP4 requires multiple lines of computational evidence to suggest no impact on gene product. REVEL (0.948) and BayesDel (0.443) both predict a deleterious effect, contradicting BP4. SpliceAI score of 0.00 indicates no splicing impact, but this does not override the missense pathogenicity predictions.	revel bayesdel spliceai
BP5	Not assessed	BP5 requires the variant to be found in a case with an alternative molecular basis for disease. No such data are available.
BP6	Not assessed	BP6 requires a reputable source to have recently classified this variant as benign. The variant is absent from ClinVar; no such classification exists.	clinvar
BP7	N/A	BP7 applies only to synonymous (silent) variants for which splicing prediction algorithms predict no splice impact. NM_001982.3:c.244G>A is a missense variant (p.Glu82Lys), not a synonymous variant. BP7 is not applicable to missense changes.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions. This variant is a single-nucleotide substitution, not an in-frame indel.
PM3	N/A	PM3 requires detection of the variant in trans with a known pathogenic variant for recessive disorders. No phase data or trans configuration information is available, and the primary ERBB3 disease association (biallelic LOF syndrome, PMID:31752936) lacks a curated pathogenic variant set to anchor the PM3 analysis.
PM4	N/A	PM4 applies to protein length changes (in-frame deletions/insertions, stop-loss variants) in non-repeat regions. This variant is a single-nucleotide missense substitution, not a protein-length-altering variant.

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