ERBB3c.994G>AUncertain significance

Print report

Variant interpretation report

ERBB3 c.994G>A, p.(Glu332Lys)

NM_001982.4:c.994G>A NP_001973.2:p.(Glu332Lys) View identifiers

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.

About ERBB3

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 supporting (benign) · 1 moderate (pathogenic) · 2 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 27 Aug 2026 · version 7.0.6

Evidence considered

View criteria

Applied evidence criteria

PM1 (moderate): The variant alters ERBB3 residue Glu332, a statistically significant single-residue hotspot (cancerhotspots.org, Q-value 4.75e-7; Chang et al. 2017) confirmed by OncoKB as a statistically significant hotspot, satisfying PM1.
PM2 (supporting): The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population databases, meeting PM2 (allele frequency < 0.1%).
PP3 (supporting): In silico tools favor a deleterious effect (REVEL 0.614; BayesDel 0.108), while SpliceAI predicts no splicing impact (max delta 0.01); PP3 is met at supporting strength.
BP1 (supporting): Germline ERBB3 disease is associated with biallelic loss-of-function variants; missense variants are not an established germline disease mechanism, so BP1 (missense variant in a gene where primarily truncating variants cause disease) applies at supporting benign strength.

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: 3 Benign evidence criteria: 1

Pathogenic criteria applied · 3

PM1Moderate

PM1 · moderate

The variant alters ERBB3 residue Glu332, a statistically significant single-residue hotspot (cancerhotspots.org, Q-value 4.75e-7; Chang et al. 2017) confirmed by OncoKB as a statistically significant hotspot, satisfying PM1.

PM2Supporting

PM2 · supporting

The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population databases, meeting PM2 (allele frequency < 0.1%).

PP3Supporting

PP3 · supporting

In silico tools favor a deleterious effect (REVEL 0.614; BayesDel 0.108), while SpliceAI predicts no splicing impact (max delta 0.01); PP3 is met at supporting strength.

Benign criteria applied · 1

BP1Supporting

BP1 · supporting

Germline ERBB3 disease is associated with biallelic loss-of-function variants; missense variants are not an established germline disease mechanism, so BP1 (missense variant in a gene where primarily truncating variants cause disease) applies at supporting benign strength.

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: PM1 moderate, PM2 supporting, PP3 supporting, BP1 supporting benign; combination = 1 moderate + 2 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

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.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.008 maximum delta

Recorded SpliceAI maximum delta score: 0.008. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

39 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV57246601, n = 39 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 4 met · 20 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_001982.4:c.994G>A (p.Glu332Lys) is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population databases (PM2).

The variant affects ERBB3 residue Glu332, a statistically significant single-residue hotspot (cancerhotspots.org Q-value 4.75e-7) confirmed by OncoKB, satisfying PM1.

In silico predictors REVEL (0.614) and BayesDel (0.108) favor a deleterious missense effect while SpliceAI predicts no splicing impact, supporting PP3.

Germline ERBB3 disease is associated with biallelic loss-of-function variants; missense variants are not an established germline disease mechanism, supporting BP1.

No germline functional, segregation, de novo, case-control, or ClinVar evidence is available; the combined evidence (PM1 + PM2 + PP3 versus BP1) is insufficient for a likely pathogenic or likely benign call, and the variant is classified as a Variant of Uncertain Significance (VUS).

Met · 4

PM1 ModerateThe variant alters ERBB3 residue Glu332, a statistically significant single-residue hotspot (cancerhotspots.org, Q-value 4.75e-7; Chang et al. 2017) confirmed by OncoKB as a statistically significant hotspot, satisfying PM1. Details ▾Hide ▴

Evidence considered

cancerhotspots.org: ERBB3 E332 single-residue hotspot
Q-value 4.75e-7 (Chang et al. 2017)
OncoKB confirms 'identified as a statistically significant hotspot'
COSMIC COSV57246601 reported 39 times.

Still missing

The exact variant E332K is not individually listed in cancerhotspots.org (residue-level significance only).

Sources

oncokb ↗

PM2 SupportingThe variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population databases, meeting PM2 (allele frequency < 0.1%). Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (exome)
gnomAD v4.1 (exome)
and gnomAD-Canada v1.0 (genomes).

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PP3 SupportingIn silico tools favor a deleterious effect (REVEL 0.614; BayesDel 0.108), while SpliceAI predicts no splicing impact (max delta 0.01); PP3 is met at supporting strength. Details ▾Hide ▴

Evidence considered

REVEL 0.614 (damaging-leaning)
BayesDel noAF 0.108
SpliceAI max delta 0.008 (no splice impact).

Still missing

REVEL score is only moderately elevated (0.614)
BayesDel noAF threshold is not verified in this pipeline
HCI prior unavailable.

Sources

revelbayesdelspliceai ↗

BP1 SupportingGermline ERBB3 disease is associated with biallelic loss-of-function variants; missense variants are not an established germline disease mechanism, so BP1 (missense variant in a gene where primarily truncating variants cause disease) applies at supporting benign strength. Details ▾Hide ▴

Evidence considered

Germline ERBB3 disease = biallelic loss-of-function multisystem syndrome (PMID 31752936)
missense is not the established germline mechanism.

Still missing

This variant is a recurrent somatic oncogenic hotspot (gain-of-function context)
which is outside the germline loss-of-function disease model
germline missense constraint data are not available.

Sources

pvs1_gene_context

Not met · 20 · evaluated, threshold not reached

PS1 No previously established pathogenic variant with the same amino acid change (p.Glu332Lys) was identified; the variant is absent from ClinVar. Details ▾Hide ▴

Evidence considered

Variant absent from ClinVar
no established pathogenic variant with identical amino acid change.

Still missing

No established pathogenic variant database entry at this residue.

Sources

clinvar ↗

PS2 No de novo occurrence with confirmed parentage has been reported for this variant. Details ▾Hide ▴

Evidence considered

No de novo report identified in any reviewed source.

Still missing

No parental/family testing data available.

PS3 No variant-specific functional data exist; OncoKB explicitly states no functional data are available for ERBB3 E332K, and no functional study was identified in the reviewed literature. Details ▾Hide ▴

Evidence considered

OncoKB: 'There is no available functional data about the ERBB3 E332K mutation' (last reviewed 02/02/2023)
labeled Likely Oncogenic on hotspot basis only.

Still missing

No experimental functional characterization of this variant.

Sources

oncokb ↗

PS4 No case-control or affected-cohort prevalence data are available to assess enrichment of this variant in affected individuals. Details ▾Hide ▴

Evidence considered

No affected-individual prevalence or case-control data.

Still missing

No cohort/case-control data.

PM5 No different pathogenic missense variant at the same residue (Glu332) was identified to serve as a comparator; PM5 is not met. Details ▾Hide ▴

Evidence considered

No same-residue comparator variants identified (0 candidates)
variant absent from ClinVar.

Still missing

No established pathogenic variant at residue 332.

Sources

pm5_candidates

PM6 No de novo observation (without confirmed parentage) has been reported for this variant. Details ▾Hide ▴

Evidence considered

No de novo report identified.

Still missing

No family/parentage data.

PP1 No cosegregation data with disease in affected family members are available. Details ▾Hide ▴

Evidence considered

No cosegregation data.

Still missing

No family segregation data.

PP2 Missense is not an established germline disease mechanism for ERBB3 (germline disease is biallelic loss-of-function), and there is no evidence of a low benign missense rate in this gene. Details ▾Hide ▴

Evidence considered

Germline ERBB3 disease mechanism is biallelic loss-of-function
not missense.

Still missing

No gene-level missense constraint data.

Sources

pvs1_gene_context

PP4 No patient phenotype or family history specific to an ERBB3-related disorder was available for assessment. Details ▾Hide ▴

Evidence considered

No phenotype/family history data provided.

Still missing

No clinical phenotype data.

PP5 No reputable source (e.g., ClinVar expert panel) reports this variant as pathogenic; the variant is absent from ClinVar. Details ▾Hide ▴

Evidence considered

Variant absent from ClinVar
no expert-panel or reputable-source pathogenicity assertion.

Sources

clinvar ↗

BA1 The variant is absent from population databases, far below the BA1 (>1%) allele frequency threshold. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 and v4.1 (0%).

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 The variant is absent from population databases, below the BS1 (>0.3%) allele frequency threshold. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 and v4.1 (0%).

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 The variant has not been observed in healthy adults; it is absent from gnomAD, so BS2 is not met. Details ▾Hide ▴

Evidence considered

Not observed in healthy adult population databases.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS3 No well-established functional studies demonstrating a benign (non-deleterious) effect exist; no functional data are available for this variant. Details ▾Hide ▴

Evidence considered

OncoKB states no functional data are available for ERBB3 E332K.

Still missing

No functional data.

Sources

oncokb ↗

BS4 No segregation data demonstrating absence of cosegregation with disease are available. Details ▾Hide ▴

Evidence considered

No segregation data.

Still missing

No family segregation data.

BP2 No observation of this variant in trans with a pathogenic variant (or cis with a pathogenic variant in a recessive disorder) is available. Details ▾Hide ▴

Evidence considered

No co-occurrence/phase data.

Still missing

No phase/co-occurrence data.

BP4 In silico predictors do not support a benign effect (REVEL 0.614 and BayesDel 0.108 favor deleterious); BP4 is not met. Details ▾Hide ▴

Evidence considered

REVEL 0.614 and BayesDel 0.108 favor deleterious
SpliceAI neutral (max delta 0.008).

Sources

revelbayesdelspliceai ↗

BP5 No case in which the variant co-occurs with an alternate molecular basis for disease was identified. Details ▾Hide ▴

Evidence considered

No alternate molecular basis data.

BP6 No reputable source reports this variant as benign; the variant is absent from ClinVar. Details ▾Hide ▴

Evidence considered

Variant absent from ClinVar
no benign assertion.

Sources

clinvar ↗

PS5 No evidence satisfies PS5; no established pathogenic attribution or equivalent source for this variant was identified. Details ▾Hide ▴

Evidence considered

No supporting evidence identified.

Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/ANM_001982.4:c.994G>A is a missense substitution (p.Glu332Lys), not a null variant; PVS1 applies only to loss-of-function variants (nonsense, frameshift, canonical +/-1,2 splice, or initiation codon), so this criterion is not applicable. Details ▾Hide ▴

Evidence considered

Missense variant (p.Glu332Lys)
variant bucket 'other'
not a null-variant bucket per the generic PVS1 framework (PMC6185798).

Sources

pvs1_variant_assessment

PM3 N/ANo recessive disorder with a pathogenic variant in trans was identified for this variant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AMissense substitution, not a protein-length-altering in-frame indel or stop-loss variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/AMissense substitution, not an in-frame deletion/insertion in a repetitive region. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant (p.Glu332Lys), not a synonymous variant; BP7 is not applicable. Details ▾Hide ▴

Evidence considered

Missense substitution (Glu->Lys).

Identifiers

Gene: ERBB3
Transcript: NM_001982.4
Coding (HGVS c.): NM_001982.4:c.994G>A
Protein (HGVS p.): NP_001973.2:p.(Glu332Lys)
GRCh38: chr12:56088753 G>A
GRCh37: chr12:56482537 G>A
COSMIC: COSV57246601

Gene diagram

Every interpreted variant in ERBB3, mapped onto the exon structure of NM_001982.4. Select a row to find it on the plot.

ERBB3NM_001982.4

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

SpliceAI acceptor lossat +10 bp

0.003

SpliceAI acceptor gainat +3 bp

0.004

SpliceAI donor lossat +115 bp

0.002

SpliceAI donor gainat -127 bp

0.008

Pangolin splice lossmagnitude shown

-0.008

Pangolin splice gain

0.004

Other predictors

REVEL: 0.614
BayesDel: 0.108

How the predictions were used

Evidence considered

REVEL 0.614 (damaging-leaning)
BayesDel noAF 0.108
SpliceAI max delta 0.008 (no splice impact).

Still missing

REVEL score is only moderately elevated (0.614)
BayesDel noAF threshold is not verified in this pipeline
HCI prior unavailable.

Sources

revelbayesdelspliceai ↗

BP4 In silico predictors do not support a benign effect (REVEL 0.614 and BayesDel 0.108 favor deleterious); BP4 is not met. Details ▾Hide ▴

Evidence considered

REVEL 0.614 and BayesDel 0.108 favor deleterious
SpliceAI neutral (max delta 0.008).

Sources

revelbayesdelspliceai ↗

BP7 N/AThis is a missense variant (p.Glu332Lys), not a synonymous variant; BP7 is not applicable. Details ▾Hide ▴

Evidence considered

Missense substitution (Glu->Lys).

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.614. BayesDel score = 0.107745.

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 0.008 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

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). REVEL score = 0.614. BayesDel score = 0.107745.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57246601, n = 39 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.