NM_004448.3:c.256A>G

ERBB2 · NP_004439.2:p.(Ile86Val) · NM_004448.3

GRCh37: chr17:37864604 A>G · GRCh38: chr17:39708351 A>G

Gene: ERBB2 Transcript: NM_004448.3

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

ERBB2

Transcript

NM_004448.3

Protein

NP_004439.2:p.(Ile86Val)

gnomAD AF

3.531519743054058e-05 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_004448.3:c.256A>G (p.Ile86Val) in ERBB2 is absent from ClinVar and is present at very low frequency in population databases (gnomAD v2.1 AF=0.0068%, v4.1 AF=0.0035%), meeting PM2 at supporting strength.

Multiple in silico predictors do not support a deleterious effect: REVEL score is 0.249, BayesDel score is -0.268, and SpliceAI predicts no splicing impact (max delta 0.01), meeting BP4 at supporting strength.

No variant-specific functional studies (PS3/BS3), de novo observations (PS2/PM6), co-segregation data (PP1/BS4), case-control data (PS4), or clinical phenotype data (PP4) were identified. The variant does not lie in a statistically significant hotspot (PM1 not met).

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence for pathogenicity and benign impact are balanced. The variant is classified as a Variant of Uncertain Significance (VUS) per generic ACMG/AMP 2015 combination rules.

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	N/A	NM_004448.3:c.256A>G is a missense variant (p.Ile86Val) and does not fall into any default PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The generic PVS1 framework (PMC6185798) does not apply to missense variants.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	No alternative nucleotide change at c.256 resulting in the same p.Ile86Val amino acid change has been identified in ClinVar or the literature. Insufficient data to assess PS1.
PS2	Not assessed	No de novo data available for this variant. No family studies or trio sequencing data were identified.
PS3	Not assessed	No variant-specific functional studies were identified. OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No publications with functional data for NM_004448.3:c.256A>G were found.	oncokb
PS4	Not assessed	No case-control studies comparing variant prevalence in affected versus unaffected individuals were identified. The variant is absent from ClinVar, providing no case-level observational data.	clinvar
PS5	Not assessed	PS5 is assessed only when PM5 criteria are met and the comparator variant is classified as pathogenic. No same-residue comparator variants were identified; PM5 is not applicable, precluding PS5 assessment.	pm5_candidates
PM1	Not met	Residue 86 lies in the extracellular domain of ERBB2, not in a statistically significant mutational hotspot. The hotspots analysis confirmed this variant does not lie in a statistically significant hotspot. No evidence that p.Ile86 is a critical functional domain residue.
PM2	Met	This variant is present at very low frequency in population databases. In gnomAD v2.1, the allele frequency is 0.00676% (17/251,362 alleles, 0 homozygotes) with a grpmax filtering allele frequency of 0.0302%. In gnomAD v4.1, the allele frequency is 0.00353% (57/1,614,036 alleles) with a grpmax FAF of 0.0437%. Both are well below the 0.1% threshold for PM2 supporting.	gnomad_v2 gnomad_v4
PM5	N/A	Unable to confirm classic same-residue PM5 semantics — no same-residue comparator variants (different amino acid change at p.Ile86) identified in ClinVar or literature. PM5 candidate harvesting returned zero candidates.	pm5_candidates
PM6	Not assessed	No de novo data available. No publications reporting de novo occurrence of NM_004448.3:c.256A>G with confirmed maternity/paternity were identified.
PP1	Not assessed	No co-segregation data available. No family studies demonstrating segregation of NM_004448.3:c.256A>G with disease were identified.
PP2	Not assessed	While ERBB2 has a loss-of-function disease mechanism supported by germline literature, specific gene-level constraint metrics (e.g., missense Z-score) were not retrieved for this case. ERBB2 is a well-characterized oncogene in which activating missense variants are a known somatic mechanism, complicating the straightforward application of PP2 in a germline context without dedicated constraint data.
PP3	Not met	Multiple in silico tools do not support a deleterious effect. REVEL score is 0.249 (below the 0.5 threshold for pathogenic prediction). BayesDel score is -0.268 (below 0.0, consistent with a benign prediction). SpliceAI max delta score is 0.01 (no predicted splicing impact). The consensus of in silico predictors does not support pathogenicity.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or clinical data specific to this variant were available for review. The variant is absent from ClinVar, providing no phenotype-level case data.	clinvar
PP5	Not assessed	This variant is absent from ClinVar. No reputable source (clinical laboratory, expert panel, or published report) has classified this variant as pathogenic.	clinvar
BA1	Not met	The variant does not meet the BA1 allele frequency threshold (>1%). In gnomAD v2.1, the overall AF is 0.00676% and in gnomAD v4.1, the overall AF is 0.00353%. The highest subpopulation frequency is 0.056% in gnomAD v4.1 South Asian. All frequencies are well below 1%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant does not meet the BS1 allele frequency threshold (>0.3%). In gnomAD v2.1, the overall AF is 0.00676% with grpmax FAF of 0.0302%. In gnomAD v4.1, the overall AF is 0.00353% with grpmax FAF of 0.0437%. All frequencies are well below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	One homozygous individual is observed in gnomAD v4.1 (South Asian population, 1 homozygote out of 91,080 alleles). However, BS2 requires confirmed observation in a healthy adult individual. gnomAD is a population database that does not provide individual-level phenotype confirmation. The homozygous observation is noted but does not independently satisfy BS2 without clinical confirmation of unaffected status.	gnomad_v4
BS3	Not assessed	No variant-specific functional studies demonstrating no damaging effect on protein function or splicing were identified. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence.	oncokb
BS4	Not assessed	No segregation data available. No family studies demonstrating lack of segregation of NM_004448.3:c.256A>G with disease in affected family members were identified.
BP1	Not met	BP1 applies to genes where primarily truncating variants cause disease. ERBB2 is a well-established oncogene in which missense activating variants (particularly in the kinase domain) are a well-recognized pathogenic mechanism. Missense variants are a known mechanism of disease in ERBB2; the gene is not limited to a truncation-only disease mechanism.
BP2	Not assessed	No data available regarding observation of this variant in trans with a known pathogenic variant. No phase information or family studies are available.
BP4	Met	Multiple in silico tools predict no significant impact. REVEL score is 0.249 (below 0.5, not consistent with pathogenicity). BayesDel score is -0.268 (below 0.0, consistent with a benign prediction). SpliceAI max delta score is 0.01 (no predicted splicing alteration). The consensus of computational predictors supports a benign interpretation.	revel bayesdel spliceai
BP5	Not assessed	No case reports identifying an alternate molecular basis for disease in an individual harboring this variant were identified.
BP6	Not assessed	This variant is absent from ClinVar. No reputable source has classified this variant as benign or likely benign.	clinvar
BP7	N/A	NM_004448.3:c.256A>G is a missense variant (p.Ile86Val), not a synonymous or intronic variant. BP7 applies only to synonymous/non-coding variants for which splicing prediction algorithms predict no impact.
BP3	N/A	This is a single-nucleotide substitution, not an in-frame deletion or insertion. BP3 applies only to in-frame indels in repeat regions without a known function.
PM3	N/A	PM3 applies to recessive disorders requiring biallelic observations. The current germline disease context for ERBB2 does not indicate a clearly established biallelic/recessive inheritance pattern; dominant or de novo models are more consistent with available literature.
PM4	N/A	This is a single-nucleotide missense variant. PM4 applies to protein length-altering variants (in-frame deletions/insertions, stop-loss). No protein length change results from this substitution.

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