NM_001982.3:c.1008_1010delTGGinsCCA

ERBB3 · NP_001973.2:p.(Gly337Gln) · NM_001982.3

GRCh37: chr12:56482551 TGG>CCA · GRCh38: chr12:56088767 TGG>CCA

Gene: ERBB3 Transcript: NM_001982.3

Final call

VUS

PM2 supporting

Variant details

Gene

ERBB3

Transcript

NM_001982.3

Protein

NP_001973.2:p.(Gly337Gln)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001982.3:c.1008_1010delTGGinsCCA (p.Gly337Gln) in ERBB3 was assessed using the generic ACMG/AMP 2015 framework (PMID:25741868).

PVS1 is not applicable: the variant produces a single missense substitution, not a null variant in a gene where loss of function is a known disease mechanism.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0.0). PM2 is met at supporting strength.

The variant is absent from ClinVar with no functional data, no de novo observations, no case-control studies, no segregation data, and no in silico scores applicable. All other criteria are not met, not applicable, or not assessed.

With only PM2_supporting met, the variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 combination 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	NM_001982.3:c.1008_1010delTGGinsCCA (normalized: c.1008_1010inv) is a 3-bp inversion resulting in a single missense substitution p.(Gly337Gln). It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The ClinGen SVI PVS1 decision tree (PMC6185798) does not apply.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	PS1 requires a different nucleotide change producing the same amino acid change as an established pathogenic variant. No pathogenic missense variant at residue Gly337 has been established in ClinVar or the literature; the variant is absent from ClinVar entirely.	clinvar
PS2	Not met	No de novo observations have been reported for NM_001982.3:c.1008_1010delTGGinsCCA in ClinVar, denovo-db, or published literature. A targeted exploratory search returned no candidate de novo events.	clinvar
PS3	Not assessed	No variant-specific functional data are available for p.(Gly337Gln). A gene-level functional characterization of somatic ERBB3 extracellular domain mutations (PMID:26266863) did not include this variant. No deep mutational scanning data in MaveDB.
PS4	Not met	No case-control studies or significantly enriched allele counts in affected cohorts versus controls are available. The variant is absent from gnomAD (v2.1, v4.1, Canada), precluding statistical comparison. A well-powered association study is not feasible for a variant this rare.	gnomad_v2 gnomad_v4 gnomad_canada
PS5	N/A	PS5 requires a novel missense variant at an amino acid residue where a different missense change has been established as pathogenic. ERBB3 p.(Gly337Gln) is not a novel change at a residue with a known pathogenic comparator; the variant and the residue have no established pathogenic entries in ClinVar.	clinvar
PM1	Not met	Residue 337 lies at the beginning of the L2 ligand-binding domain (residues 335–497), a functionally important extracellular domain. Cancerhotspots.org identifies this residue as a statistically significant somatic hotspot, and gnomAD shows no population variation at this position. However, no ClinGen-approved PM1 domain specification exists for ERBB3, and somatic hotspot data alone is insufficient to meet PM1 in a germline ACMG/AMP context without supporting germline pathogenic enrichment data.
PM2	Met	NM_001982.3:c.1008_1010delTGGinsCCA is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). The allele frequency is 0.0 in all population databases, well below the PM2 threshold of <0.1%, supporting that this is a rare variant not observed in large population cohorts.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 applies to protein length changes resulting from in-frame deletions/insertions in non-repeat regions or stop-loss variants. NM_001982.3:c.1008_1010delTGGinsCCA is a 3-bp inversion resulting in a single missense substitution p.(Gly337Gln) with no net change in protein length.
PM5	N/A	PM5 requires a different pathogenic missense change at the same residue (Gly337). No comparator variants were identified — ClinVar has no entries at this residue, and automated PM5 candidate harvesting returned zero candidates. No alternative pathogenic amino acid substitution at Gly337 has been reported.	pm5_candidates clinvar
PM6	Not met	No de novo observations have been reported. Exploratory search found no affected individuals carrying this variant with absent or unknown parental testing. All known ERBB3 pathogenic variants linked to congenital contracture syndromes are inherited in a recessive manner, making PM6 less applicable overall.	clinvar
PP1	Not met	No multi-generational pedigrees with multiple affected members segregating this variant have been published. Cosegregation analysis is not possible without family data.
PP2	Not met	PP2 requires a missense variant in a gene with a low rate of benign missense variation and where missense variants are a common disease mechanism. While ERBB3 missense variants have been implicated in disease (e.g., erythroid MDS predisposition), no HCI prior or gnomAD constraint metric data were available for ERBB3 in this case. Without established constraint metrics, PP2 cannot be reliably applied.
PP3	Not met	In silico predictors for missense variants (REVEL, BayesDel) are not available for this indel/inversion variant. SpliceAI predicts no significant splice impact (max delta score = 0.01), which is expected for a missense variant not near splice junctions. No computational evidence supports a deleterious effect on the gene product.	spliceai
PP4	Not met	No phenotype or family history data are available to assess whether the variant is observed in a patient with a phenotype specific for ERBB3-related disease. Absent from ClinVar means no patient-level phenotype annotations exist.
PP5	N/A	PP5 requires the variant to be reported as pathogenic by a reputable source (e.g., clinical diagnostic laboratory with established expertise). The variant is entirely absent from ClinVar, with no submissions from any source.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF = 0.0). This is well below the BA1 threshold of >1% allele frequency.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all population databases (AF = 0.0), well below the BS1 threshold of >0.3% allele frequency.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. The variant is absent from gnomAD, meaning no healthy adult carriers have been observed. This criterion cannot be met.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	No functional studies demonstrating that p.(Gly337Gln) has no deleterious effect on protein function are available. A gene-level functional characterization (PMID:26266863) did not include this variant. No deep mutational scanning scores in MaveDB.
BS4	Not met	No families have been reported where the variant fails to segregate with the disease phenotype (i.e., affected individuals not carrying the variant, or unaffected individuals carrying the variant). The extreme rarity of this variant makes non-segregation data unlikely to exist.
BP1	Not met	BP1 applies to missense variants in genes for which primarily truncating variants are known to cause disease. ERBB3-related disorders have been associated with both loss-of-function truncating variants (biallelic, causing a multisystem syndrome) and missense variants (e.g., germline missense variant linked to erythroid MDS/erythroleukemia, PMID:27416908). The gene does not have 'primarily' truncating variants as its disease mechanism.
BP2	Not met	BP2 requires observation of this variant in trans with a known pathogenic variant in an unaffected individual, or in cis with a pathogenic variant in a gene with a dominant mechanism. No such observations exist; the variant is absent from ClinVar and gnomAD.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. NM_001982.3:c.1008_1010delTGGinsCCA is a 3-bp inversion in the L2 ligand-binding domain (a critical functional domain), not a deletion/insertion in a repetitive region without known function.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on the gene product. SpliceAI predicts no splicing impact (max delta = 0.01), but this is expected for a missense variant and does not assess protein-level effects. REVEL and BayesDel scores are unavailable for this indel/inversion. A single splice prediction tool is insufficient to meet BP4.	spliceai
BP5	N/A	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data exist — the variant has not been reported in any clinical case.
BP6	N/A	BP6 requires a reputable source to report the variant as benign. The variant is absent from ClinVar; no diagnostic laboratory or expert panel has classified it.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_001982.3:c.1008_1010delTGGinsCCA is a missense variant (p.Gly337Gln), not a synonymous variant.

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