LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-11
Case ID: NM_004448.3_c.2584A_G_20260811_013512
Framework: ACMG/AMP 2015
Variant classification summary

NM_004448.3:c.2584A>G

ERBB2  · NP_004439.2:p.(Thr862Ala)  · NM_004448.3
GRCh37: chr17:37881392 A>G  ·  GRCh38: chr17:39725139 A>G
Gene: ERBB2 Transcript: NM_004448.3
Final call
Likely Pathogenic
PS3 strong PM1 moderate PM2 supporting PP3 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
ERBB2
Transcript
NM_004448.3
Protein
NP_004439.2:p.(Thr862Ala)
gnomAD AF
ClinVar
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PS3 (Strong): well-established assays showed enhanced JNK/ERK signaling, anchorage-independent growth, and relative lapatinib resistance (~125 nM vs ~30 nM WT IC50).
2
PM1 (Moderate): residue 862 sits in the ERBB2 tyrosine kinase activation-loop domain, a statistically significant cancer hotspot.
3
PM2 (Supporting): variant is absent (AF = 0) from gnomAD v2.1, v4.1, and gnomAD-Canada.
4
PP3 (Supporting): REVEL score 0.674 falls within the calibrated supporting band (0.644-0.773).
5
Overall: Likely Pathogenic under generic ACMG/AMP 2015, combining 1 strong + 1 moderate + 2 supporting criteria ('1 PS + 1 PM' rule).
Final determination: Generic ACMG/AMP 2015 fallback rules classify the variant as Likely Pathogenic: 1 strong (PS3) + 1 moderate (PM1) + 2 supporting (PM2, PP3) satisfies the Likely Pathogenic combination '1 strong + 1 moderate' (and '1 strong + 2 supporting'), while no Pathogenic combination threshold (1 strong + 3 moderate; 1 strong + 2 moderate + 2 supporting; 1 strong + 1 moderate + 4 supporting) is reached.
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: this is a missense change, so no null-variant mechanism (nonsense-mediated decay or truncation) is triggered.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not met Not met: no other nucleotide change producing p.Thr862Ala is documented; c.2584A>G is the only single-nucleotide change that yields this amino acid.
clinvar pm5_candidates PMID:22046346
PS2 Not assessed Not assessed: no de novo occurrence with confirmed parentage is reported for this variant.
clinvar gnomad_v2 gnomad_v4 PMID:22046346 PMID:26619011 PMID:28572459 PMID:29420467
PS3 Met Met (strong): well-established functional assays showed enhanced JNK/ERK signaling, increased colony formation, and relative lapatinib resistance (~125 nM vs ~30 nM WT IC50).
PMID:22046346 oncokb
PS4 Not assessed Not assessed: no case-control study comparing affected individuals with controls is available; only somatic recurrence data exist.
clinvar oncokb PMID:22046346 PMID:26619011 PMID:28572459 PMID:29420467
PM1 Met Met (moderate): residue 862 lies in the ERBB2 tyrosine kinase activation-loop domain and is a statistically significant cancer hotspot (27 somatic COSMIC occurrences).
PMID:22046346 PMID:26619011 PMID:29420467 oncokb gnomad_v2 gnomad_v4 gnomad_canada clinvar
PM2 Met Met (supporting): absent (AF = 0) from gnomAD v2.1, v4.1, and gnomAD-Canada. Flagged for human review: as a recurrent somatic oncogenic hotspot, this absence may be non-informative for germline pathogenicity.
gnomad_v2 gnomad_v4 gnomad_canada oncokb
PM3 Not assessed Not assessed: no allele-phase data or recessive ERBB2 disease context is available to evaluate trans configuration.
generic_acmg_combination_rules clinvar gnomad_v2 gnomad_v4 oncokb pvs1_gene_context
PM4 N/A Not applicable: this missense change does not alter protein length, so the criterion does not apply.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not met Not met: no alternate missense at residue 862 with established pathogenicity is documented.
clinvar pm5_candidates PMID:22046346
PM6 Not assessed Not assessed: no de novo occurrence (with or without parental confirmation) is reported.
clinvar gnomad_v2 gnomad_v4 PMID:22046346 PMID:26619011 PMID:28572459 PMID:29420467
PP1 Not assessed Not assessed: no family segregation data exist for this variant.
clinvar gnomad_v2 gnomad_v4 PMID:22046346 PMID:26619011 PMID:28572459 PMID:29420467
PP2 Not met Not met: ERBB2 has no established germline disease in which missense variants are a common mechanism.
oncokb PMID:29420467 PMID:22046346
PP3 Met Met (supporting): REVEL score 0.674 falls within the ClinGen-calibrated PP3 supporting band (0.644-0.773).
revel spliceai bayesdel
PP4 Not assessed Not assessed: no proband phenotype or family history is available to evaluate.
PP5 Not met Not met: the variant is absent from ClinVar, so no expert-panel pathogenic classification exists.
clinvar
BA1 Not met Not met: allele frequency is 0 in every queried population dataset, far below the >5% benign stand-alone threshold.
gnomad_v2 gnomad_v4 gnomad_canada
BS1 Not met Not met: absent from all queried population databases (AF = 0), so it cannot exceed any disorder-expected frequency.
gnomad_v2 gnomad_v4 gnomad_canada
BS2 Not met Not met: no heterozygous or homozygous observations exist in any population dataset or ClinVar.
gnomad_v2 gnomad_v4 gnomad_canada clinvar
BS3 Not met Not met: functional studies demonstrate enhanced activation and transforming activity, the opposite of a benign effect.
BS4 Not assessed Not assessed: no data on absence of the variant in affected family members are available.
clinvar gnomad_v2 gnomad_v4 PMID:22046346 PMID:26619011 PMID:28572459 PMID:29420467
BP1 Not met Not met: ERBB2 disease relevance is somatic gain-of-function oncogenesis, not primarily truncating variants.
oncokb PMID:29420467 PMID:22046346
BP2 Not assessed Not assessed: no allele-phase observations relative to a pathogenic variant are available.
generic_acmg_combination_rules clinvar gnomad_v2 gnomad_v4 oncokb pvs1_gene_context
BP3 N/A Not applicable: this criterion applies to in-frame indels in repetitive regions, not missense changes.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: REVEL score 0.674 is far above the BP4 supporting upper threshold of 0.183.
revel spliceai bayesdel
BP5 Not assessed Not assessed: no case-level data show an alternate molecular diagnosis for a carrier.
BP6 Not met Not met: the variant is absent from ClinVar, so no expert-panel benign classification exists.
clinvar
BP7 N/A Not applicable: this criterion applies to synonymous variants; this is a missense change.
generic_acmg_combination_rules
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