NM_001982.3:c.1008_1010delTGGinsCCA (p.Gly337Gln) in ERBB3 was assessed using the generic ACMG/AMP 2015 framework (PMID:25741868).1 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.2 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0.0). PM2 is met at supporting strength.3 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.4 With only PM2_supporting met, the variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 combination rules.5
ERBB3
Final classification
VUS
ERBB3 c.1008_1010inv · p.Gly337Gln
ERBB3
NM_001982.3:c.1008_1010delTGGinsCCA (p.Gly337Gln) in ERBB3 was assessed using the generic ACMG/AMP 2015 framework (PMID:25741868).
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 supporting; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2
VUS
ERBB3 c.1008_1010inv
PM2
→
VUS
1
generic_acmg_combination_rules
5
generic_acmg_combination_rules
Gene diagram
· NM_001982.3 · variants mapped to exon structure
ERBB3
NM_001982.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 17 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1 (AF = 0.0)Absent from gnomAD v4.1 (AF = 0.0)Absent from gnomAD-Canada v1.0 (AF = 0.0)
Assessed · not applied
Pathogenic
PS2
No de novo observations have been reported for NM_001982.3:c.1008_1010delTGGinsCCA in ClinVar, denovo-db, or published literature.
PS3
No variant-specific functional data are available for p.(Gly337Gln).
PS4
No case-control studies or significantly enriched allele counts in affected cohorts versus controls are available.
PM1
Residue 337 lies at the beginning of the L2 ligand-binding domain (residues 335–497), a functionally important extracellular domain.
PM6
No de novo observations have been reported.
PP1
No multi-generational pedigrees with multiple affected members segregating this variant have been published.
PP2
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.
PP3
In silico predictors for missense variants (REVEL, BayesDel) are not available for this indel/inversion variant.
PP4
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.
Benign
BA1
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF = 0.0).
BS1
The variant is absent from all population databases (AF = 0.0), well below the BS1 threshold of >0.3% allele frequency.
BS2
BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age.
BS3
No functional studies demonstrating that p.(Gly337Gln) has no deleterious effect on protein function are available.
BS4
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).
BP1
BP1 applies to missense variants in genes for which primarily truncating variants are known to cause disease.
BP2
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.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact on the gene product.
N/A · 9
PVS1 · PS1 · PM4 · PM5 · PP5 · BP3 · BP5 · BP6 · 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).
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. ERBB3, a receptor tyrosine kinase, is altered by mutation or amplification in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant lies in a statistically significant hotspot.
Sources & reference links