Variant classification summary

NM_004448.4:c.2329G>T

ERBB2 · NP_004439.2:p.(Val777Leu) · NM_004448.4

GRCh37: chr17:37881000 G>T · GRCh38: chr17:39724747 G>T

Gene: ERBB2 Transcript: NM_004448.4

Final call

VUS

PS3 strong PM1 moderate PM2 supporting BP4 supporting BP5 supporting

Variant details

Gene

ERBB2

Transcript

NM_004448.4

Protein

NP_004439.2:p.(Val777Leu)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 strong: p.Val777Leu increased ERBB2 kinase activity, signaling, transformation, and xenograft growth versus wild type.

2

PM1 moderate: Val777 is in the ERBB2 kinase domain, with functional effects and no gnomAD observation.

3

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1.

4

BP4 supporting: REVEL 0.284 is at or below the generic BP4 threshold of 0.29.

5

BP5 supporting: the reported V777L carcinoma also carried S310F, an alternate molecular basis.

Final determination: Generic ACMG/AMP 2015 fallback rules yield Likely Pathogenic from PS3 strong plus PM1 moderate plus PM2 supporting and Likely Benign from BP4 supporting plus BP5 supporting; satisfying both sides makes the final call 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 met	Not met: evidence shows ERBB2 p.Val777Leu itself, but no established pathogenic alternate nucleotide change producing the same amino-acid substitution.	clinvar PMID:23220880 PMID:22046346 PMID:24516025
PS2	Not assessed	Not assessed: no germline proband with confirmed maternity and paternity, disease phenotype, and no family history is documented.
PS3	Met	Met, strong: ERBB2 p.Val777Leu increased kinase activity, signaling, soft-agar growth, and xenograft tumor growth versus wild type across two functional studies.	PMID:23220880 PMID:22046346
PS4	Not met	Not met: no qualifying exact-V777L case-control comparison provided an odds ratio satisfying OR > 5.0 with a 95% confidence interval excluding 1.0.
PM1	Met	Met at moderate strength: Val777 lies in the ERBB2 kinase domain, with direct functional effects and absence from gnomAD v2.1 and v4.1.	PMID:23220880 PMID:22046346 PMID:24516025 PMID:29420467 gnomad_v2 gnomad_v4
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, with observed allele frequency 0 versus the PM2 threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband, second pathogenic allele, or parental/offspring phase result establishes this variant in trans for a recessive disorder.
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 met	Not met: residue 777 is recurrently mutated, but no different missense substitution at Val777 is established as pathogenic in the reviewed evidence.	PMID:23220880 PMID:26619011 PMID:29420467 pm5_candidates
PM6	Not assessed	Not assessed: no proband-level assumed de novo germline occurrence is documented without parental confirmation.
PP1	Not assessed	Not assessed: no affected relatives or informative meioses showing cosegregation with the variant are documented.
PP2	Not assessed	Not assessed: variant absence and somatic gain of function do not establish ERBB2's low benign-missense rate and common disease-causing missense mechanism.	gnomad_v2 gnomad_v4
PP3	Not met	Not met: REVEL 0.284 is below the >=0.644 generic PP3 supporting threshold for this missense variant.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family-history description establishes a highly specific disease with a single genetic etiology.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification; the available record is single-submitter uncertain significance.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, giving filtering allele frequency 0 versus the BA1 threshold of >=0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 show filtering allele frequency 0, below the generic BS1 threshold of >=0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy adult carrier, homozygote, or hemizygote observation is available to evaluate the BS2 requirement.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: Two studies showed increased ERBB2 kinase signaling and transforming activity for p.Val777Leu rather than a no-damaging functional effect.	PMID:23220880 PMID:22046346
BS4	Not assessed	Not assessed: no affected family members with variant testing are documented to evaluate lack of segregation.
BP1	Not assessed	Not assessed: available somatic missense evidence does not establish that ERBB2 disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no pathogenic partner variant or cis/trans phase result supports either BP2 pathway in this case.
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	Met	Met at supporting: REVEL 0.284 is at or below the <=0.29 generic BP4 threshold for this missense variant.	revel
BP5	Met	Met, supporting: the exact V777L tumor also carried S310F at approximately 47% allele frequency, providing an alternate molecular basis in the reported carcinoma.	PMID:24516025
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present.	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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