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 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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