About ERBB3
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ERBB3 c.244G>A, p.(Glu82Lys)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Moderate
PM2 · moderate
NM_001982.3:c.244G>A is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada. Complete absence from large population databases (allele frequency 0%, well below the 0.1% threshold for PM2) constitutes moderate evidence of pathogenicity under the ACMG/AMP 2015 framework.
PP3Supporting
PP3 · supporting
Multiple in silico predictors support a deleterious effect. REVEL score of 0.948 (strongly pathogenic) and BayesDel score of 0.443 (intermediate, leaning deleterious). SpliceAI predicts no splice impact (max delta 0.00), which is expected for an exonic missense. The convergence of REVEL and BayesDel toward a damaging prediction meets PP3 at supporting strength.
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 moderate, PP3 supporting; combination = 1 moderate + 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
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. 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. 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 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_001982.3:c.244G>A (p.Glu82Lys) is a missense variant in ERBB3 exon 3.
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (0 alleles across all populations), meeting PM2 at moderate strength.
Multiple in silico predictors support a deleterious effect: REVEL score 0.948 (strongly pathogenic) and BayesDel score 0.443 (intermediate, leaning deleterious), meeting PP3 at supporting strength.
PVS1 is not applicable as c.244G>A is a missense variant, not a null variant (nonsense, frameshift, or canonical ±1,2 splice). Per ClinGen SVI PVS1 recommendations (PMC6185798), the generic PVS1 framework applies only to predicted null variants.
The variant is absent from ClinVar, absent from COSMIC, and not located in a statistically significant mutational hotspot (CancerHotspots). No literature PMIDs were identified for this variant. OncoKB classifies it as 'Unknown Oncogenic Effect' without variant-specific functional evidence.
No de novo, segregation, case-control, functional, or phenotype-specific data are available for this variant; PS2, PS3, PS4, PP1, PP4, PM6, and benign criteria BS2-BS4, BP5-BP6 remain not assessed.
PM5 is not applicable as no pathogenic missense comparator at ERBB3 residue E82 was identified. BP7 is not applicable to missense variants.
Overall classification: 1 moderate pathogenic criterion (PM2) and 1 supporting pathogenic criterion (PP3) are met. Under the generic ACMG/AMP 2015 combination rules (PMID:25741868), this does not reach the Likely Pathogenic threshold (minimum: 3 moderate, or 2 moderate + 2 supporting, or 1 moderate + 4 supporting). The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 ModerateNM_001982.3:c.244G>A is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada. Complete absence from large population databases (allele frequency 0%, well below the 0.1% threshold for PM2) constitutes moderate evidence of pathogenicity under the ACMG/AMP 2015 framework. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles)
- gnomAD v4.1 (0 alleles)
- and gnomAD-Canada (0 alleles).
Sources
PP3 SupportingMultiple in silico predictors support a deleterious effect. REVEL score of 0.948 (strongly pathogenic) and BayesDel score of 0.443 (intermediate, leaning deleterious). SpliceAI predicts no splice impact (max delta 0.00), which is expected for an exonic missense. The convergence of REVEL and BayesDel toward a damaging prediction meets PP3 at supporting strength. Details ▾Hide ▴
Evidence considered
- REVEL: 0.948 (strongly deleterious)
- BayesDel: 0.443 (intermediate
- leaning deleterious)
- SpliceAI max delta: 0.00 (no splicing impact).
Still missing
- BayesDel score (0.443) is below typical high-confidence deleterious thresholds
- limiting PP3 strength to supporting.
Sources
Not met · 5 · evaluated, threshold not reached
PM1 PM1 requires the variant to be located in a mutational hotspot or well-established critical functional domain without benign variation. Residue E82 lies within the extracellular domain of ERBB3 (exon 3). CancerHotspots does not identify this position as statistically significant. No ClinGen- or VCEP-defined critical domain with pathogenic missense enrichment has been established for ERBB3. Details ▾Hide ▴
Evidence considered
- CancerHotspots: residue not statistically significant
- variant not in a defined critical functional domain.
BA1 BA1 requires allele frequency > 1% in population databases. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0%). Does not meet the BA1 threshold. Details ▾Hide ▴
Evidence considered
- Allele frequency 0% across all gnomAD datasets
- well below 1% BA1 threshold.
Sources
BS1 BS1 requires allele frequency greater than expected for the disorder (> 0.3% by non-VCEP criteria). The variant is absent from all gnomAD datasets (allele frequency 0%). Does not meet the BS1 threshold. Details ▾Hide ▴
Evidence considered
- Allele frequency 0% across all gnomAD datasets
- well below 0.3% BS1 threshold.
Sources
BP1 BP1 requires a missense variant in a gene for which primarily truncating variants are known to cause disease. While biallelic ERBB3 loss-of-function variants are associated with a multisystem syndrome (PMID:31752936), the literature also supports missense variants as potentially contributory to ERBB3-related phenotypes. The disease mechanism is not exclusively limited to truncating variants, so BP1 cannot be applied. Details ▾Hide ▴
Evidence considered
- ERBB3 LOF supported as disease mechanism
- but missense variants are not excluded as potentially pathogenic.
Sources
pvs1_gene_context
BP4 BP4 requires multiple lines of computational evidence to suggest no impact on gene product. REVEL (0.948) and BayesDel (0.443) both predict a deleterious effect, contradicting BP4. SpliceAI score of 0.00 indicates no splicing impact, but this does not override the missense pathogenicity predictions. Details ▾Hide ▴
Evidence considered
- REVEL 0.948 (deleterious)
- BayesDel 0.443 (leaning deleterious)
- in silico evidence supports pathogenicity
- not benign effect.
Sources
Not assessed · 16 · no assessment recorded
PS1 PS1 requires a different nucleotide change resulting in the same amino acid substitution (E82K) previously established as pathogenic. No such variant is present in ClinVar and no literature PMIDs were identified for this case. Without an established pathogenic comparator at residue 82, PS1 cannot be assessed. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no pathogenic comparator at residue E82 identified.
Still missing
- No established pathogenic missense at ERBB3 residue 82 identified in ClinVar or literature.
Sources
PS2 PS2 requires a confirmed de novo occurrence with parental confirmation. No de novo data, family studies, or trio sequencing reports are available for this variant. Details ▾Hide ▴
Still missing
- No de novo or parental confirmation data available.
PS3 PS3 requires well-established functional studies demonstrating a deleterious effect. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. No literature PMIDs with functional data were identified. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional studies identified.
Still missing
- No functional assay data (enzymatic
- ligand-binding
- signaling
- or model organism) available for E82K.
Sources
PS4 PS4 requires a statistically significant enrichment in affected individuals versus controls. No case-control or cohort prevalence data are available. The variant is absent from ClinVar and COSMIC, precluding any case-count analysis. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- COSMIC
- and all gnomAD population databases
- no affected vs. control comparison possible.
Still missing
- No case counts or cohort data available to perform statistical comparison.
Sources
PM6 PM6 requires a confirmed de novo occurrence without parental confirmation, or a de novo assumption. No de novo data are available for this variant. Details ▾Hide ▴
Still missing
- No de novo data available.
PP1 PP1 requires co-segregation of the variant with disease in multiple affected family members. No family or segregation data are available. Details ▾Hide ▴
Still missing
- No family or segregation data available.
PP2 PP2 requires the gene to have a low rate of benign missense variation and for missense variants to be a common disease mechanism. HCI Prior data are unavailable for ERBB3 (gene not supported), precluding quantitative assessment of missense constraint. While ERBB3 LOF is supported as a germline disease mechanism, the relative contribution of missense vs. truncating variants cannot be determined without constraint metrics. Details ▾Hide ▴
Evidence considered
- HCI Prior not available for ERBB3.
Still missing
- No missense constraint metric (HCI Prior) available for ERBB3.
PP4 PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. No patient phenotype information is available for this case. Details ▾Hide ▴
Still missing
- No patient phenotype or clinical indication provided.
PP5 PP5 requires a reputable source (e.g., expert panel, clinical laboratory) to have recently classified this variant as pathogenic. The variant is absent from ClinVar and no expert panel classification exists. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no expert panel or reputable source classification.
Still missing
- No expert panel or reputable source classification.
Sources
BS2 BS2 requires observation of the variant in a healthy adult for a fully penetrant dominant disorder, or observation in trans with a pathogenic variant for a recessive disorder. No phenotypic data on healthy carriers are available. Details ▾Hide ▴
Still missing
- No data on healthy adult carriers.
BS3 BS3 requires well-established functional studies demonstrating no deleterious effect. No functional studies were identified for this variant (OncoKB: Unknown Oncogenic Effect; zero literature PMIDs). Details ▾Hide ▴
Evidence considered
- No variant-specific functional studies identified.
Still missing
- No functional data demonstrating normal protein function.
Sources
BS4 BS4 requires lack of segregation of the variant with disease in affected family members. No family studies or segregation data are available. Details ▾Hide ▴
Still missing
- No segregation or family data available.
BP2 BP2 requires observation of the variant in trans with a pathogenic variant in a fully penetrant recessive disorder, or in cis with a pathogenic variant. No such data are available. Details ▾Hide ▴
Still missing
- No trans or cis phase data available.
BP5 BP5 requires the variant to be found in a case with an alternative molecular basis for disease. No such data are available. Details ▾Hide ▴
Still missing
- No alternative molecular cause data available.
BP6 BP6 requires a reputable source to have recently classified this variant as benign. The variant is absent from ClinVar; no such classification exists. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no benign classification from any reputable source.
Still missing
- No reputable source classification.
Sources
PS5 PS5 requires a reputable source (e.g., expert panel, clinical laboratory) to have recently reported this variant as pathogenic with evidence not independently available. The variant is absent from ClinVar entirely; no reputable source has classified it. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no expert panel or clinical laboratory classification exists.
Still missing
- No reputable source classification for this variant.
Sources
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001982.3:c.244G>A is a missense variant (p.Glu82Lys), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). Per the ClinGen SVI PVS1 decision tree (PMC6185798), generic PVS1 framework applies only to null variants. This missense substitution falls into the 'other' bucket and is ineligible for PVS1 adjudication. Details ▾Hide ▴
Evidence considered
- Missense G>A substitution at c.244
- producing Glu82Lys
- not a predicted null variant. PVS1 framework does not apply to missense variants.
Sources
PM3 N/APM3 requires detection of the variant in trans with a known pathogenic variant for recessive disorders. No phase data or trans configuration information is available, and the primary ERBB3 disease association (biallelic LOF syndrome, PMID:31752936) lacks a curated pathogenic variant set to anchor the PM3 analysis. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length changes (in-frame deletions/insertions, stop-loss variants) in non-repeat regions. This variant is a single-nucleotide missense substitution, not a protein-length-altering variant. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 requires a different pathogenic missense change at the same amino acid residue (E82). Automated and targeted ClinVar candidate harvesting identified zero same-residue pathogenic missense comparators at ERBB3 residue 82. PM5 cannot be applied without a qualifying comparator. Details ▾Hide ▴
Evidence considered
- Zero same-residue pathogenic missense comparator variants identified at ERBB3 E82.
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions. This variant is a single-nucleotide substitution, not an in-frame indel. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies only to synonymous (silent) variants for which splicing prediction algorithms predict no splice impact. NM_001982.3:c.244G>A is a missense variant (p.Glu82Lys), not a synonymous variant. BP7 is not applicable to missense changes. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous
- BP7 does not apply.
Identifiers
- Gene
- ERBB3
- Transcript
- NM_001982.3
- Coding (HGVS c.)
- NM_001982.3:c.244G>A
- Protein (HGVS p.)
- NP_001973.2:p.(Glu82Lys)
- GRCh38
- chr12:56085004 G>A
- GRCh37
- chr12:56478788 G>A
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in ERBB3
—
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
- 0.948
- BayesDel
- 0.443
How the predictions were used
PP3 SupportingMultiple in silico predictors support a deleterious effect. REVEL score of 0.948 (strongly pathogenic) and BayesDel score of 0.443 (intermediate, leaning deleterious). SpliceAI predicts no splice impact (max delta 0.00), which is expected for an exonic missense. The convergence of REVEL and BayesDel toward a damaging prediction meets PP3 at supporting strength. Details ▾Hide ▴
Evidence considered
- REVEL: 0.948 (strongly deleterious)
- BayesDel: 0.443 (intermediate
- leaning deleterious)
- SpliceAI max delta: 0.00 (no splicing impact).
Still missing
- BayesDel score (0.443) is below typical high-confidence deleterious thresholds
- limiting PP3 strength to supporting.
Sources
BP4 BP4 requires multiple lines of computational evidence to suggest no impact on gene product. REVEL (0.948) and BayesDel (0.443) both predict a deleterious effect, contradicting BP4. SpliceAI score of 0.00 indicates no splicing impact, but this does not override the missense pathogenicity predictions. Details ▾Hide ▴
Evidence considered
- REVEL 0.948 (deleterious)
- BayesDel 0.443 (leaning deleterious)
- in silico evidence supports pathogenicity
- not benign effect.
Sources
BP7 N/ABP7 applies only to synonymous (silent) variants for which splicing prediction algorithms predict no splice impact. NM_001982.3:c.244G>A is a missense variant (p.Glu82Lys), not a synonymous variant. BP7 is not applicable to missense changes. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous
- BP7 does not apply.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.948. BayesDel score = 0.443228.
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 0.000
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.244G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-56478788-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-56085004-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-56085004-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001982.3%3Ac.244G…
- OncoKB ↗www.oncokb.org/gene/ERBB3/E82K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ERBB3+c.244G%3EA
- 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 = 0.00). REVEL score = 0.948. BayesDel score = 0.443228.
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 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.