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.1 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.2 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).3 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.4
ERBB2
Final classification
VUS
ERBB2 c.256A>G · p.Ile86Val
ERBB2
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
ERBB2 c.256A>G
PM2 + BP4
→
VUS
Gene diagram
· NM_004448.3 · variants mapped to exon structure
ERBB2
NM_004448.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: AF=0.00676% (17/251362)0 homozygotes
✓
BP4
supporting
Benign
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: 0.249 (below 0.5 pathogenic threshold)BayesDel: -0.268 (benign prediction)SpliceAI: max delta 0.01 (no splicing impact)
Assessed · not applied
Pathogenic
PS1
No alternative nucleotide change at c.256 resulting in the same p.Ile86Val amino acid change has been identified in ClinVar or the literature.
PS2
No de novo data available for this variant.
PS3
No variant-specific functional studies were identified.
PS4
No case-control studies comparing variant prevalence in affected versus unaffected individuals were identified.
PM1
Residue 86 lies in the extracellular domain of ERBB2, not in a statistically significant mutational hotspot.
PM6
No de novo data available.
PP1
No co-segregation data available.
PP2
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.
PP3
Multiple in silico tools do not support a deleterious effect.
PP4
No patient phenotype or clinical data specific to this variant were available for review.
PP5
This variant is absent from ClinVar.
Benign
BA1
The variant does not meet the BA1 allele frequency threshold (>1%).
BS1
The variant does not meet the BS1 allele frequency threshold (>0.3%).
BS2
One homozygous individual is observed in gnomAD v4.1 (South Asian population, 1 homozygote out of 91,080 alleles).
BS3
No variant-specific functional studies demonstrating no damaging effect on protein function or splicing were identified.
BS4
No segregation data available.
BP1
BP1 applies to genes where primarily truncating variants cause disease.
BP2
No data available regarding observation of this variant in trans with a known pathogenic variant.
BP5
No case reports identifying an alternate molecular basis for disease in an individual harboring this variant were identified.
BP6
This variant is absent from ClinVar.
N/A · 6
PVS1 · PM3 · PM4 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.53152e-05; MAF= 0.00353%, 57/1614036 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000559947; MAF= 0.05599%, 51/91080 alleles, homozygotes = 1); grpmax FAF= 0.00043658.
v2.1
This variant is present in gnomAD v2.1 (AF= 6.76315e-05; MAF= 0.00676%, 17/251362 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00048994; MAF= 0.04899%, 15/30616 alleles, homozygotes = 0); grpmax FAF= 0.00030154.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0035%
· 57 / 1,614,036
1 hom · FAF 0.044%
1 hom · FAF 0.044%
South Asian 51 / 91,080 |
0.056% 1 hom |
Middle Eastern 1 / 6,084 |
0.016% |
Remaining individuals 1 / 62,486 |
0.0016% |
European (Finnish) 1 / 64,040 |
0.0016% |
European (non-Finnish) 3 / 1,180,026 |
0.00025% |
+ 5 not observed (Admixed American, Amish, East Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0068%
· 17 / 251,362
0 hom · FAF 0.03%
0 hom · FAF 0.03%
South Asian 15 / 30,616 |
0.049% |
European (non-Finnish) 2 / 113,676 |
0.0018% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
0.011%
· 2 / 18,418
0 hom · FAF 0.026%
0 hom · FAF 0.026%
South Asian 2 / 1,362 |
0.15% |
+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, European (non-Finnish), Remaining individuals)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.249. BayesDel score = -0.268367.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ERBB2, a receptor tyrosine kinase, is altered by mutation, amplification and/or overexpression in various cancer types, most frequently in breast, eso
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links