Variant classification summary

NM_004448.4:c.2033G>A

ERBB2 · NP_004439.2:p.(Arg678Gln) · NM_004448.4

GRCh37: chr17:37879658 G>A · GRCh38: chr17:39723405 G>A

Gene: ERBB2 Transcript: NM_004448.4

Final call

VUS

PS3 supporting PM1 moderate PM2 supporting

Variant details

Gene

ERBB2

Transcript

NM_004448.4

Protein

NP_004439.2:p.(Arg678Gln)

gnomAD AF

6.19525715892941e-07 (v4.1)

ClinVar

Likely oncogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: R678Q showed activation in orthogonal functional assays, although results were discordant.

2

PM1 moderate: ERBB2 R678 lies in a reported hotspot and critical transmembrane/juxtamembrane region.

3

PM2 supporting: gnomAD v4.1 AF is 6.20e-7, with one allele and zero homozygotes.

Final determination: Under the generic ACMG/AMP 2015 fallback, one moderate criterion plus two supporting criteria does not meet a pathogenic or likely pathogenic rule, and no benign rule is satisfied; therefore the call is VUS.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no previously established pathogenic variant with the same Arg678Gln amino-acid change is documented in the supplied evidence.	PMID:23220880 PMID:24971884 PMID:30449325 clinvar
PS2	Not assessed	Not assessed: no documented affected proband, confirmed maternity and paternity, or parental genotypes are available for this variant.
PS3	Met	Met, supporting: R678Q showed activation across BaF3 survival/signaling and MCF10A acinar assays, but two independent studies reported no demonstrable gain-of-function.	PMID:30449325 PMID:23220880 PMID:24971884
PS4	Not met	Not met: no affected-versus-control comparison or OR/95% CI is reported; the largest study only documents R678Q in 192 of 111,176 tumors.	PMID:23220880 PMID:24971884 PMID:29420467 PMID:29967253 PMID:30449325 gnomad_v4
PM1	Met	Met at moderate strength: ERBB2 R678 is reported in a statistically significant hotspot and lies in the transmembrane/juxtamembrane functional region.	hotspots PMID:24971884 PMID:30449325
PM2	Met	Met at supporting strength: gnomAD v4.1 AF is 6.20e-7, below the PM2 threshold of 0.0001, with one allele and zero homozygotes.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected recessive proband, pathogenic second allele, or parental/offspring testing establishing trans phase is documented.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense substitution at Arg678 is documented as pathogenic in the supplied evidence.	PMID:24971884 PMID:30449325 oncokb
PM6	Not assessed	Not assessed: no report identifies this variant as assumed de novo, and no proband or parental-testing data are available.
PP1	Not assessed	Not assessed: zero affected relatives, informative meioses, or variant-positive family members are reported for cosegregation analysis.
PP2	Not assessed	Not assessed: the supplied evidence does not establish both low benign missense variation and a common missense disease mechanism for ERBB2.	gnomad_v4 PMID:30449325
PP3	Not met	Not met: missense REVEL 0.417 is below the generic PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: the patient's phenotype and family history are not available for comparison with a disease having a highly specific single-gene presentation.
PP5	Not met	Not met: ClinVar has only a single-submitter somatic Likely oncogenic record, with no exact-variant expert-panel Pathogenic or Likely pathogenic classification.	clinvar oncokb PMID:30449325
BA1	Not met	Not met: gnomAD v4.1 frequency is 6.20e-7, far below the generic BA1 threshold of 0.05, and no grpmax FAF is reported.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 AF is 6.20e-7, far below the generic BS1 default of 0.01, with no elevated grpmax FAF reported.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD shows one allele and zero homozygotes, but lacks verified healthy-adult phenotype and age evidence required for BS2.	gnomad_v4 clinvar
BS3	Not met	Not met: although two studies found no demonstrable gain-of-function, PMID:30449325 showed R678Q activation in BaF3 and MCF10A assays.	PMID:23220880 PMID:24971884 PMID:30449325
BS4	Not assessed	Not assessed: no affected relatives with documented variant testing are available to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: no systematic evidence shows that ERBB2 disease is caused primarily by truncating rather than missense variants.	PMID:30449325
BP2	Not assessed	Not assessed: no phase-resolved observation shows this variant in trans or cis with a pathogenic variant under the BP2 definition.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL 0.417 exceeds the generic BP4 supporting threshold of 0.29.	revel
BP5	Not assessed	Not assessed: no case is documented in which this variant co-occurs with an alternate molecular basis for the disease under evaluation.	PMID:23220880 PMID:24971884 PMID:30449325 cosmic
BP6	Not met	Not met: ClinVar provides only a single-submitter somatic Likely oncogenic assertion, with no exact-variant expert-panel Benign or Likely benign classification.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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