ERBB2

Chr 17AR

erb-b2 receptor tyrosine kinase 2

Also known as: CD340, HER-2, HER-2/neu, HER2, MLN 19, MLN-19, NEU, NGL

NCBI Gene: 2064 UniProt: P04626

This gene encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. This protein has no ligand binding domain of its own and therefore cannot bind growth factors. However, it does bind tightly to other ligand-bound EGF receptor family members to form a heterodimer, stabilizing ligand binding and enhancing kinase-mediated activation of downstream signalling pathways, such as those involving mitogen-activated protein kinase and phosphatidylinositol-3 kinase. Allelic variations at amino acid positions 654 and 655 of isoform a (positions 624 and 625 of isoform b) have been reported, with the most common allele, Ile654/Ile655, shown here. Amplification and/or overexpression of this gene has been reported in numerous cancers, including breast and ovarian tumors. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

?Visceral neuropathy, familial, 2, autosomal recessiveMIM #619465

Adenocarcinoma of lung, somaticMIM #211980

Gastric cancer, somaticMIM #613659

Glioblastoma, somaticMIM #137800

Ovarian cancer, somaticMIM #167000

UniProtGlioma

UniProtLung cancer

Active trials

466

ClinVar variants

Pathogenic / LP

3.2

Missense Z· constrained

0.40

LOEUF

Pubs (2 yr)

Clinical Summary— ERBB2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.

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ClinVar Variants

13 Pathogenic / Likely Pathogenic· 272 VUS of 466 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

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GeneReview available — ERBB2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

ensembl: TimeoutError: The operation was aborted due to timeout

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.40LOEUF

pLI 0.006

Z-score 5.57

OE 0.27 (0.18–0.40)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

3.25Z-score

OE missense 0.67 (0.62–0.72)

510 obs / 762.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.27 (0.18–0.40)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.67 (0.62–0.72)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99

0≤1.21.6

LoF obs/exp: 18 / 67.3Missense obs/exp: 510 / 762.5Syn Z: 0.15

ClinVar Variant Classifications

466 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic2

VUS272

Likely Benign159

Benign18

Conflicting4

Pathogenic

Likely Pathogenic

272

VUS

159

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	3	6	0	11
Likely Pathogenic	0	0	2	0	2
VUS	9	239	20	4	272
Likely Benign	1	7	66	85	159
Benign	0	1	7	10	18
Conflicting	—				4
Total	12	250	101	99	466

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ERBB2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

ERB-B2 RECEPTOR TYROSINE KINASE 2; ERBB2

MIM #164870 · *

?Visceral neuropathy, familial, 2, autosomal recessive

MIM #619465