NM_004448.3:c.3582del

ERBB2 · NP_004439.2:p.(Glu1195SerfsTer3) · NM_004448.3

GRCh37: chr17:37884107 AC>A · GRCh38: chr17:39727854 AC>A

Gene: ERBB2 Transcript: NM_004448.3

Final call

VUS

PVS1 moderate PM2 supporting

Variant details

Gene

ERBB2

Transcript

NM_004448.3

Protein

NP_004439.2:p.(Glu1195SerfsTer3)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_004448.3:c.3582del (p.Glu1195SerfsTer3) is a frameshift deletion in exon 27 of ERBB2, the last exon, predicted to truncate 58 C-terminal residues without triggering nonsense-mediated decay.

Under the ClinGen SVI PVS1 framework (PMC6185798), the variant qualifies for PVS1 at moderate strength: a frameshift in the last exon where NMD is not predicted and the truncated region (<10% of the protein) does not contain a critical functional domain — the kinase domain remains intact.

The variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), supporting PM2 at supporting strength.

No functional studies, case-control data, de novo observations, cosegregation data, or ClinVar classifications are available for this variant. Computational splicing prediction (SpliceAI max delta = 0.00) is neutral.

The combined evidence (PVS1_Moderate + PM2_Supporting) yields 1 moderate and 1 supporting criterion. Under generic ACMG/AMP 2015 combination rules, this does not meet the threshold for Likely Pathogenic (requires ≥1 moderate + ≥4 supporting, or ≥2 moderate + ≥2 supporting, among other combinations). The variant is classified as a Variant of Uncertain Significance (VUS).

Human review is recommended: ERBB2 is a proto-oncogene where C-terminal truncations have been associated with gain-of-function in somatic contexts, and the evidence for germline ERBB2 loss-of-function as a disease mechanism is limited.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	Met	NM_004448.3:c.3582del is a frameshift deletion in exon 27/27 (the last exon) of ERBB2, predicted to result in p.(Glu1195SerfsTer3) with loss of 58 C-terminal residues (1195-1255). The variant is located in the last exon and is not predicted to undergo nonsense-mediated decay. Under PMC6185798, for frameshift variants where NMD is not expected and the truncated region (<10% of the protein) does not remove a critical functional domain (the kinase domain, aa 720-987, remains intact), PVS1 is applied at moderate strength. Germline ERBB2 loss-of-function is supported as a disease mechanism by targeted literature review, though the supporting evidence is predominantly derived from related ERBB-family genes and somatic cancer contexts.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment gnomad_v2 gnomad_v4
PS1	N/A	PS1 applies when the same amino acid change has been independently established as pathogenic. This variant is a frameshift deletion, not a missense variant.
PS2	Not met	No de novo occurrence data is available for this variant.
PS3	Not met	No functional studies testing NM_004448.3:c.3582del or a systematically characterized range that includes this position were identified in the literature.
PS4	Not met	No case-control data or statistical evidence of enrichment in affected individuals is available for this variant.
PS5	N/A	PS5 is not part of the standard ACMG/AMP 2015 criteria set.
PM1	Not met	The variant does not lie within a statistically significant mutational hotspot as determined by cancerhotspots.org. The C-terminal tail of ERBB2, while containing regulatory phosphorylation sites, is not a well-established critical functional domain for PM1 purposes under generic ACMG/AMP — no domain-level pathogenic variant cluster has been demonstrated in this region.
PM2	Met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with a rare pathogenic variant. Under generic ACMG/AMP, absence from population databases (allele frequency <0.1%) supports PM2 at supporting strength.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 applies to in-frame deletions/insertions in non-repeat regions and stop-loss variants. NM_004448.3:c.3582del is a frameshift (out-of-frame) deletion, which is evaluated under PVS1 rather than PM4.
PM5	N/A	PM5 requires a same-residue missense comparator with established pathogenicity. This is a frameshift variant; no same-residue missense comparator candidates were identified. The automated PM5 candidate harvest returned no eligible comparators.	pm5_candidates
PM6	Not met	No de novo occurrence data is available for this variant.
PP1	Not met	No cosegregation data with disease is available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. NM_004448.3:c.3582del is a frameshift deletion, not a missense variant.
PP3	Not met	SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL and BayesDel are not applicable to non-SNV variants. No computational evidence supports a deleterious effect.	spliceai
PP4	Not met	No patient-specific phenotype or family history data is available for assessment.
PP5	Not met	This variant is absent from ClinVar; no reputable source has reported it as pathogenic.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Population allele frequency is well below the 1% threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD. Population allele frequency is well below the 0.3% threshold for BS1.	gnomad_v2 gnomad_v4
BS2	Not met	Not observed in a healthy adult homozygous or hemizygous state. No such observations are reported in population databases.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrating a benign effect for this variant are available.
BS4	Not met	No cosegregation data demonstrating absence of segregation with disease is available.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants cause disease. NM_004448.3:c.3582del is itself a truncating (frameshift) variant, not a missense.
BP2	Not met	No evidence of this variant occurring in trans with a known pathogenic variant in a recessive disorder.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. NM_004448.3:c.3582del is an out-of-frame (frameshift) deletion.
BP4	Not met	SpliceAI predicts no splicing impact (max delta = 0.00), but NM_004448.3:c.3582del is a frameshift variant with a clear predicted protein-truncating effect (p.Glu1195SerfsTer3). Computational evidence does not support a benign interpretation — a frameshift with premature termination is inherently predicted to be damaging.	spliceai
BP5	Not met	No alternative molecular cause has been identified in a case harboring this variant.
BP6	Not met	This variant is absent from ClinVar; no reputable source has reported it as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants without predicted splicing impact. NM_004448.3:c.3582del is a frameshift deletion, not a synonymous variant.

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.