About ERBB3
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ERBB3 c.1008_1010inv, p.(Gly337Gln)
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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_001982.3:c.1008_1010delTGGinsCCA is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). The allele frequency is 0.0 in all population databases, well below the PM2 threshold of <0.1%, supporting that this is a rare variant not observed in large population cohorts.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
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; combination = 1 supporting, 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
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. ERBB3, a receptor tyrosine kinase, is altered by mutation or amplification in various cancer types.
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 lies 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.
28 criteria with recorded statuses: 1 met · 15 not met · 2 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001982.3:c.1008_1010delTGGinsCCA (p.Gly337Gln) in ERBB3 was assessed using the generic ACMG/AMP 2015 framework (PMID:25741868).
PVS1 is not applicable: the variant produces a single missense substitution, not a null variant in a gene where loss of function is a known disease mechanism.
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0.0). PM2 is met at supporting strength.
The variant is absent from ClinVar with no functional data, no de novo observations, no case-control studies, no segregation data, and no in silico scores applicable. All other criteria are not met, not applicable, or not assessed.
With only PM2_supporting met, the variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 combination rules.
No criteria match.
Met · 1
PM2 SupportingNM_001982.3:c.1008_1010delTGGinsCCA is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). The allele frequency is 0.0 in all population databases, well below the PM2 threshold of <0.1%, supporting that this is a rare variant not observed in large population cohorts. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF = 0.0)
- Absent from gnomAD v4.1 (AF = 0.0)
- Absent from gnomAD-Canada v1.0 (AF = 0.0)
Sources
Not met · 15 · evaluated, threshold not reached
PS2 No de novo observations have been reported for NM_001982.3:c.1008_1010delTGGinsCCA in ClinVar, denovo-db, or published literature. A targeted exploratory search returned no candidate de novo events. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no de novo submissions
- Exploratory literature search yielded no de novo reports
Still missing
- No denovo-db or DECIPHER query results
- directed search for ERBB3 de novo variants in congenital contracture or cancer predisposition syndromes may be warranted
Sources
PS4 No case-control studies or significantly enriched allele counts in affected cohorts versus controls are available. The variant is absent from gnomAD (v2.1, v4.1, Canada), precluding statistical comparison. A well-powered association study is not feasible for a variant this rare. Details ▾Hide ▴
Evidence considered
- Variant absent from all population databases
- no case-control enrichment data
Still missing
- No affected cohort screening data available
Sources
PM1 Residue 337 lies at the beginning of the L2 ligand-binding domain (residues 335–497), a functionally important extracellular domain. Cancerhotspots.org identifies this residue as a statistically significant somatic hotspot, and gnomAD shows no population variation at this position. However, no ClinGen-approved PM1 domain specification exists for ERBB3, and somatic hotspot data alone is insufficient to meet PM1 in a germline ACMG/AMP context without supporting germline pathogenic enrichment data. Details ▾Hide ▴
Evidence considered
- Residue 337 falls within the L2 ligand-binding domain (critical for neuregulin binding and receptor dimerization)
- Cancerhotspots.org identifies this residue as statistically significant in somatic context
- No benign germline variation observed at this position in gnomAD
Still missing
- No ClinGen-approved PM1 domain specification for ERBB3
- No germline mutational hotspot established for this residue
PM6 No de novo observations have been reported. Exploratory search found no affected individuals carrying this variant with absent or unknown parental testing. All known ERBB3 pathogenic variants linked to congenital contracture syndromes are inherited in a recessive manner, making PM6 less applicable overall. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar or published literature
Still missing
- The variant has not been observed in any proband
- with or without parental testing
Sources
PP1 No multi-generational pedigrees with multiple affected members segregating this variant have been published. Cosegregation analysis is not possible without family data. Details ▾Hide ▴
Still missing
- No cosegregation data from affected families
PP2 PP2 requires a missense variant in a gene with a low rate of benign missense variation and where missense variants are a common disease mechanism. While ERBB3 missense variants have been implicated in disease (e.g., erythroid MDS predisposition), no HCI prior or gnomAD constraint metric data were available for ERBB3 in this case. Without established constraint metrics, PP2 cannot be reliably applied. Details ▾Hide ▴
Evidence considered
- HCI prior not available for ERBB3 (gene_not_supported)
Still missing
- No gnomAD missense constraint Z-score or o/e metric retrieved for ERBB3
PP3 In silico predictors for missense variants (REVEL, BayesDel) are not available for this indel/inversion variant. SpliceAI predicts no significant splice impact (max delta score = 0.01), which is expected for a missense variant not near splice junctions. No computational evidence supports a deleterious effect on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL: not available (not an SNV)
- BayesDel: not available (not an SNV)
- SpliceAI max delta = 0.01 (no predicted splicing impact)
Still missing
- No protein-level in silico scores available for this variant class
Sources
PP4 No phenotype or family history data are available to assess whether the variant is observed in a patient with a phenotype specific for ERBB3-related disease. Absent from ClinVar means no patient-level phenotype annotations exist. Details ▾Hide ▴
Still missing
- No phenotype data associated with this variant
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF = 0.0). This is well below the BA1 threshold of >1% allele frequency. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 0.0 (<1%)
- gnomAD v4.1 AF = 0.0 (<1%)
- gnomAD-Canada AF = 0.0 (<1%)
Sources
BS1 The variant is absent from all population databases (AF = 0.0), well below the BS1 threshold of >0.3% allele frequency. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 0.0 (<0.3%)
- gnomAD v4.1 AF = 0.0 (<0.3%)
- gnomAD-Canada AF = 0.0 (<0.3%)
Sources
BS2 BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. The variant is absent from gnomAD, meaning no healthy adult carriers have been observed. This criterion cannot be met. Details ▾Hide ▴
Evidence considered
- Variant absent from all population databases
- no healthy adult carriers observed
Sources
BS4 No families have been reported where the variant fails to segregate with the disease phenotype (i.e., affected individuals not carrying the variant, or unaffected individuals carrying the variant). The extreme rarity of this variant makes non-segregation data unlikely to exist. Details ▾Hide ▴
Still missing
- No segregation or non-segregation data available
BP1 BP1 applies to missense variants in genes for which primarily truncating variants are known to cause disease. ERBB3-related disorders have been associated with both loss-of-function truncating variants (biallelic, causing a multisystem syndrome) and missense variants (e.g., germline missense variant linked to erythroid MDS/erythroleukemia, PMID:27416908). The gene does not have 'primarily' truncating variants as its disease mechanism. Details ▾Hide ▴
Evidence considered
- ERBB3 disease mechanism includes both truncating and missense variants
Sources
BP2 BP2 requires observation of this variant in trans with a known pathogenic variant in an unaffected individual, or in cis with a pathogenic variant in a gene with a dominant mechanism. No such observations exist; the variant is absent from ClinVar and gnomAD. Details ▾Hide ▴
Still missing
- No trans configuration data in healthy controls
- No cis configuration data with a dominant pathogenic variant
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene product. SpliceAI predicts no splicing impact (max delta = 0.01), but this is expected for a missense variant and does not assess protein-level effects. REVEL and BayesDel scores are unavailable for this indel/inversion. A single splice prediction tool is insufficient to meet BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01 (no splicing impact predicted)
- REVEL and BayesDel unavailable for this variant class
Still missing
- No protein-level computational predictors available
- Only one computational tool (SpliceAI) assessable
- insufficient for BP4 threshold
Sources
Not assessed · 2 · no assessment recorded
PS3 No variant-specific functional data are available for p.(Gly337Gln). A gene-level functional characterization of somatic ERBB3 extracellular domain mutations (PMID:26266863) did not include this variant. No deep mutational scanning data in MaveDB. Details ▾Hide ▴
Evidence considered
- One gene-level functional study identified (PMID:26266863) — does not include p.Gly337Gln
- MaveDB: no ERBB3 deep mutational scanning data found
Still missing
- No in vitro functional assay for p.Gly337Gln
- no high-throughput mutagenesis scores available
Sources
BS3 No functional studies demonstrating that p.(Gly337Gln) has no deleterious effect on protein function are available. A gene-level functional characterization (PMID:26266863) did not include this variant. No deep mutational scanning scores in MaveDB. Details ▾Hide ▴
Evidence considered
- No variant-specific functional data available
Still missing
- No in vitro or in vivo functional assay for p.Gly337Gln
- No deep mutational scanning data for ERBB3 in MaveDB
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001982.3:c.1008_1010delTGGinsCCA (normalized: c.1008_1010inv) is a 3-bp inversion resulting in a single missense substitution p.(Gly337Gln). It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The ClinGen SVI PVS1 decision tree (PMC6185798) does not apply. Details ▾Hide ▴
Evidence considered
- Variant classified as missense (p.Gly337Gln) via Mutalyzer normalization
- Variant bucket: 'other' — not a null variant
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/APS1 requires a different nucleotide change producing the same amino acid change as an established pathogenic variant. No pathogenic missense variant at residue Gly337 has been established in ClinVar or the literature; the variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no established pathogenic comparator at this residue
Sources
PM4 N/APM4 applies to protein length changes resulting from in-frame deletions/insertions in non-repeat regions or stop-loss variants. NM_001982.3:c.1008_1010delTGGinsCCA is a 3-bp inversion resulting in a single missense substitution p.(Gly337Gln) with no net change in protein length. Details ▾Hide ▴
Evidence considered
- Variant is a 3-bp inversion producing a missense change
- protein length unchanged
PM5 N/APM5 requires a different pathogenic missense change at the same residue (Gly337). No comparator variants were identified — ClinVar has no entries at this residue, and automated PM5 candidate harvesting returned zero candidates. No alternative pathogenic amino acid substitution at Gly337 has been reported. Details ▾Hide ▴
Evidence considered
- Zero same-residue comparator variants found in ClinVar
- PM5 candidate harvesting returned no eligible candidates
Sources
pm5_candidatesclinvar ↗
PP5 N/APP5 requires the variant to be reported as pathogenic by a reputable source (e.g., clinical diagnostic laboratory with established expertise). The variant is entirely absent from ClinVar, with no submissions from any source. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no reputable source reports it as pathogenic
Sources
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. NM_001982.3:c.1008_1010delTGGinsCCA is a 3-bp inversion in the L2 ligand-binding domain (a critical functional domain), not a deletion/insertion in a repetitive region without known function. Details ▾Hide ▴
Evidence considered
- Variant is an inversion
- not a deletion/insertion in a repetitive region
BP5 N/ABP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data exist — the variant has not been reported in any clinical case. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ABP6 requires a reputable source to report the variant as benign. The variant is absent from ClinVar; no diagnostic laboratory or expert panel has classified it. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no benign classification from any reputable source
Sources
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_001982.3:c.1008_1010delTGGinsCCA is a missense variant (p.Gly337Gln), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Gly337Gln)
- not synonymous
PS5 N/APS5 requires a novel missense variant at an amino acid residue where a different missense change has been established as pathogenic. ERBB3 p.(Gly337Gln) is not a novel change at a residue with a known pathogenic comparator; the variant and the residue have no established pathogenic entries in ClinVar. Details ▾Hide ▴
Identifiers
- Gene
- ERBB3
- Transcript
- NM_001982.3
- Coding (HGVS c.)
- NM_001982.3:c.1008_1010inv
- Protein (HGVS p.)
- NP_001973.2:p.(Gly337Gln)
- GRCh38
- chr12:56088767 TGG>CCA
- GRCh37
- chr12:56482551 TGG>CCA
Gene diagram
Every interpreted variant in ERBB3, mapped onto the exon structure of NM_001982.3. Select a row to find it on the plot.
ERBB3NM_001982.3
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 ERBB3
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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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 In silico predictors for missense variants (REVEL, BayesDel) are not available for this indel/inversion variant. SpliceAI predicts no significant splice impact (max delta score = 0.01), which is expected for a missense variant not near splice junctions. No computational evidence supports a deleterious effect on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL: not available (not an SNV)
- BayesDel: not available (not an SNV)
- SpliceAI max delta = 0.01 (no predicted splicing impact)
Still missing
- No protein-level in silico scores available for this variant class
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene product. SpliceAI predicts no splicing impact (max delta = 0.01), but this is expected for a missense variant and does not assess protein-level effects. REVEL and BayesDel scores are unavailable for this indel/inversion. A single splice prediction tool is insufficient to meet BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01 (no splicing impact predicted)
- REVEL and BayesDel unavailable for this variant class
Still missing
- No protein-level computational predictors available
- Only one computational tool (SpliceAI) assessable
- insufficient for BP4 threshold
Sources
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_001982.3:c.1008_1010delTGGinsCCA is a missense variant (p.Gly337Gln), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Gly337Gln)
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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
Captured gnomAD v4.1 source record
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_001982.3%3Ac.1008_1010del…
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-56482551-TGG-CCA?dataset=g…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-56088767-TGG-CCA?datase…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-56088767-TGG-CCA
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001982.3%3Ac.1008…
- OncoKB ↗www.oncokb.org/gene/ERBB3/G337Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ERBB3+c.1008_1010inv
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ERBB3, a receptor tyrosine kinase, is altered by mutation or amplification in various cancer types.
Somatic
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant lies in a statistically significant hotspot.