About ERBB2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ERBB2 c.256A>G, p.(Ile86Val)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
57 / 1,614,036 alleles
gnomAD v4.1: 57 / 1,614,036 alleles. Recorded AF 3.53152e-05. Recorded homozygote count 1.
gnomAD 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.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 5 not met · 16 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
No criteria match.
Met · 2
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.00676% (17/251
- 362)
- 0 homozygotes
- grpmax FAF=0.0302%
- gnomAD v4.1: AF=0.00353% (57/1
- 614
- 036)
- 1 homozygote (South Asian)
- grpmax FAF=0.0437%
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.249 (below 0.5 pathogenic threshold)
- BayesDel: -0.268 (benign prediction)
- SpliceAI: max delta 0.01 (no splicing impact)
Sources
Not met · 5 · evaluated, threshold not reached
PM1 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. Details ▾Hide ▴
Evidence considered
- Hotspots analysis: variant does not lie in a statistically significant hotspot
- residue 86 is in the extracellular domain
- not a recognized critical functional domain.
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.249 (below 0.5 pathogenic threshold)
- BayesDel: -0.268 (benign-leaning)
- SpliceAI: max delta 0.01 (no splicing impact)
Sources
BA1 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%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 overall AF: 0.00676%
- gnomAD v4.1 overall AF: 0.00353%
- Highest subpopulation AF: 0.056% (v4.1 South Asian)
Sources
BS1 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%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF: 0.00676%
- grpmax FAF: 0.0302%
- gnomAD v4.1 AF: 0.00353%
- grpmax FAF: 0.0437%
Sources
BP1 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. Details ▾Hide ▴
Evidence considered
- ERBB2 missense activating mutations are a known pathogenic mechanism
- gene is not limited to truncation-only disease.
Not assessed · 16 · no assessment recorded
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. Insufficient data to assess PS1. Details ▾Hide ▴
Still missing
- No same-amino-acid different-nucleotide variant identified at this position.
PS2 No de novo data available for this variant. No family studies or trio sequencing data were identified. Details ▾Hide ▴
Still missing
- No de novo or parental confirmation data available.
PS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional studies identified.
Still missing
- No published functional studies evaluating the impact of p.Ile86Val on ERBB2 protein function.
Sources
PS4 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. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no case-control data available.
Still missing
- No case-control or cohort enrichment data available.
Sources
PM6 No de novo data available. No publications reporting de novo occurrence of NM_004448.3:c.256A>G with confirmed maternity/paternity were identified. Details ▾Hide ▴
Still missing
- No de novo confirmation data available.
PP1 No co-segregation data available. No family studies demonstrating segregation of NM_004448.3:c.256A>G with disease were identified. Details ▾Hide ▴
Still missing
- No co-segregation or family 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. 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. Details ▾Hide ▴
Still missing
- No ERBB2 gene-level missense constraint metrics (e.g.
- gnomAD Z-score) available for PP2 assessment.
PP4 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. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no patient phenotype data available.
Still missing
- No patient phenotype or clinical case data available.
Sources
PP5 This variant is absent from ClinVar. No reputable source (clinical laboratory, expert panel, or published report) has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no reputable pathogenic classification available.
Still missing
- No reputable source classification available.
Sources
BS2 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. Details ▾Hide ▴
Evidence considered
- One homozygous individual in gnomAD v4.1 South Asian population (51/91
- 080 alleles
- 1 homozygote).
Still missing
- No confirmed healthy adult phenotype for the homozygous individual in gnomAD.
Sources
BS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no benign functional evidence identified.
Still missing
- No functional studies demonstrating normal protein function or splicing for this variant.
Sources
BS4 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. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP2 No data available regarding observation of this variant in trans with a known pathogenic variant. No phase information or family studies are available. Details ▾Hide ▴
Still missing
- No trans observation data available.
BP5 No case reports identifying an alternate molecular basis for disease in an individual harboring this variant were identified. Details ▾Hide ▴
Still missing
- No alternate molecular basis data available.
BP6 This variant is absent from ClinVar. No reputable source has classified this variant as benign or likely benign. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no reputable benign classification available.
Still missing
- No reputable source benign classification available.
Sources
PS5 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. Details ▾Hide ▴
Evidence considered
- No PM5-eligible comparator variant found
- PS5 cannot be assessed.
Still missing
- No same-residue pathogenic comparator variant identified at position 86.
Sources
pm5_candidates
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null variant eligible for PVS1.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 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. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AThis 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. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AUnable 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. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic missense comparator identified at position 86.
Sources
pm5_candidates
BP3 N/AThis 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. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous/non-coding variants.
Identifiers
- Gene
- ERBB2
- Transcript
- NM_004448.3
- Coding (HGVS c.)
- NM_004448.3:c.256A>G
- Protein (HGVS p.)
- NP_004439.2:p.(Ile86Val)
- GRCh38
- chr17:39708351 A>G
- GRCh37
- chr17:37864604 A>G
Gene diagram
Every interpreted variant in ERBB2, mapped onto the exon structure of NM_004448.3. Select a row to find it on the plot.
ERBB2NM_004448.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in ERBB2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
57 / 1,614,036 alleles
AF 3.53e-05 · 1 homozygotes · FAF 0.000437
gnomAD v2.1
17 / 251,362 alleles
AF 6.76e-05 · 0 homozygotes · FAF 0.000302
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 3.5e-05 · 57 / 1,614,036 alleles · 1 hom · FAF 0.00044
| South Asian51 / 91,080 | 0.000561 hom |
| Middle Eastern1 / 6,084 | 0.00016 |
| Remaining individuals1 / 62,486 | 1.6e-05 |
| European (Finnish)1 / 64,040 | 1.6e-05 |
| European (non-Finnish)3 / 1,180,026 | 2.5e-06 |
0 alternate alleles recorded in 5 other groups: Admixed American, Amish, East Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 6.8e-05 · 17 / 251,362 alleles · 0 hom · FAF 0.0003
| South Asian15 / 30,616 | 0.00049 |
| European (non-Finnish)2 / 113,676 | 1.8e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD 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.
gnomAD 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.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.249
- BayesDel
- -0.268
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.249 (below 0.5 pathogenic threshold)
- BayesDel: -0.268 (benign prediction)
- SpliceAI: max delta 0.01 (no splicing impact)
Sources
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.249 (below 0.5 pathogenic threshold)
- BayesDel: -0.268 (benign-leaning)
- SpliceAI: max delta 0.01 (no splicing impact)
Sources
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous/non-coding variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.249. BayesDel score = -0.268367.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
57 / 1,614,036 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_004448.3%3Ac.256A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-37864604-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-39708351-A-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-39708351-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004448.3%3Ac.256A…
- OncoKB ↗www.oncokb.org/gene/ERBB2/I86V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ERBB2+c.256A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).
ClinVar
This variant is absent from ClinVar.
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
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
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.