Variant classification summary

NM_004448.4:c.2313_2324dup

ERBB2 · NP_004439.2:p.(Tyr772_Ala775dup) · NM_004448.4

GRCh37: chr17:37880981 A>AGCATACGTGATG · GRCh38: chr17:39724728 A>AGCATACGTGATG

Gene: ERBB2 Transcript: NM_004448.4

Final call

Likely Pathogenic

PS3 strong PM4 moderate PM2 supporting

Variant details

Gene

ERBB2

Transcript

NM_004448.4

Protein

NP_004439.2:p.(Tyr772_Ala775dup)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic evidence: PS3 strong shows increased HER2 kinase activity and oncogenic phenotypes in controlled functional assays.

2

Pathogenic evidence: PM4 moderate reflects a four-amino-acid in-frame duplication in the structured ERBB2 kinase domain.

3

Pathogenic evidence: PM2 supporting reflects absence of the exact variant from gnomAD v2.1 and v4.1.

Final determination: Under the generic ACMG/AMP 2015 fallback, one Strong pathogenic criterion plus one Moderate pathogenic criterion supports Likely Pathogenic; PM2 supporting is additional and no benign rule is satisfied.

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 an in-frame indel.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no germline proband, family-history, or parental testing data establish confirmed maternity and paternity for a de novo occurrence.	PMID:29420467
PS3	Met	Met, strong: the corresponding HER2 insertion showed at least five-fold greater kinase-dead EGFR phosphorylation and tumors in 4/6 mice versus none for wild-type or vector controls.	PMID:16843263
PS4	Not met	Not met: reported frequencies are 10% or 12.0% in affected cancer cohorts, but no qualifying unaffected-control comparison or OR >5.0 with a confidence interval excluding 1.0 is available.	PMID:29420467
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the supplied PM2 frequency threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no recessive ERBB2 disease, affected-proband observation, pathogenic partner, or parental/offspring phase testing is documented.	clinvar
PM4	Met	Met: In-frame 12-bp duplication adds four amino acids (p.Tyr772_Ala775dup) in ERBB2's structured exon-20 kinase domain, not a repetitive region.
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: somatic cancer evidence supplies no germline proband or parental data supporting an assumed de novo occurrence.	PMID:29420467
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or familial genotype-phenotype segregation data are reported.	PMID:29420467
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
PP3	N/A	Not applicable: the exonic in-frame duplication is outside generic PP3 scope, which covers missense or intronic/splice-region variants only.
PP4	Not assessed	Not assessed: no patient phenotype or family-history details establish a highly specific disease with a single genetic etiology.
PP5	Not met	Not met: the exact ClinVar record is single-submitter with zero expert-panel submissions, so it cannot trigger PP5 under the required rule.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no grpmax FAF reaching the BA1 threshold of 0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no filtering allele frequency exceeds the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy adult carrier or inheritance-specific homozygous, heterozygous, or hemizygous observation is reported for this variant.
BS3	Not met	Not met: the available assays showed increased HER2 kinase activity and oncogenic phenotypes, not no damaging effect on protein function or splicing.	PMID:16843263
BS4	Not assessed	Not assessed: no affected relatives or familial genotypes are available to demonstrate lack of segregation.	PMID:29420467
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no germline phase result shows this variant in trans or cis with a pathogenic variant in the required inheritance context.	clinvar
BP3	Not met	Not met: Although the change is an in-frame duplication, it lies in ERBB2's known functional tyrosine-kinase domain rather than a repetitive region without known function.
BP4	N/A	Not applicable: the exonic in-frame duplication is outside generic BP4 scope, which covers missense or intronic/splice-region variants only.
BP5	Not assessed	Not assessed: cancer-cohort reports do not document an individual case with a separate molecular basis explaining the disease.
BP6	Not met	Not met: ClinVar has zero expert-panel submissions and no exact-variant benign or likely-benign expert-panel classification.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is an in-frame indel.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.