ESR1

Chr 6ADAR

estrogen receptor 1

Also known as: ER, ESR, ESRA, ESTRR, Era, NR3A1

NCBI Gene: 2099 ENSG00000091831 UniProt: P03372 OMIM: 133430

The estrogen receptor 1 protein functions as a ligand-activated transcription factor that regulates estrogen-responsive genes involved in growth, metabolism, and sexual development. Mutations cause estrogen resistance syndrome with autosomal recessive inheritance, while some variants may contribute to migraine susceptibility with autosomal dominant inheritance. This gene is highly constrained against loss-of-function variation (pLI 0.99, LOEUF 0.19), indicating that complete loss of function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an estrogen receptor and ligand-activated transcription factor. The canonical protein contains an N-terminal ligand-independent transactivation domain, a central DNA binding domain, a hinge domain, and a C-terminal ligand-dependent transactivation domain. The protein localizes to the nucleus where it may form either a homodimer or a heterodimer with estrogen receptor 2. The protein encoded by this gene regulates the transcription of many estrogen-inducible genes that play a role in growth, metabolism, sexual development, gestation, and other reproductive functions and is expressed in many non-reproductive tissues. The receptor encoded by this gene plays a key role in breast cancer, endometrial cancer, and osteoporosis. This gene is reported to have dozens of transcript variants due to the use of alternate promoters and alternative splicing, however, the full-length nature of many of these variants remain uncertain. [provided by RefSeq, Jul 2020]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.194 OMIM phenotypes

Clinical Summary— ESR1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 86 VUS of 231 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.19LOEUF

pLI 0.999

Z-score 4.45

OE 0.04 (0.01–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.61Z-score

OE missense 0.75 (0.68–0.84)

258 obs / 341.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.19)

0≤0.351.4

Missense OE?0.75 (0.68–0.84)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 1 / 25.0Missense obs/exp: 258 / 341.9Syn Z: -1.24

This gene — mechanism propensity

0.5181th %ile

GOF

0.4776th %ile

LOF

0.81top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 40% of P/LP variants are LoF · LOEUF 0.19

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNUsing a luciferase assay, we found that mRNA encoding a truncated ESR1 significantly attenuates gene expression at estrogen-response elements demonstrating a dominant negative function.1

GOFIn the past 2 years, several studies unveiled gain-of-function mutations in ESR1, the gene encoding the ER, in approximately 20% of patients with metastatic ER-positive disease who received endocrine therapies, such as tamoxifen and aromatase inhibitors.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

231 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic2

VUS86

Likely Benign69

Benign47

Conflicting6

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	2	0	0	3
Likely Pathogenic	1	1	0	0	2
VUS	2	70	13	1	86
Likely Benign	1	7	28	33	69
Benign	0	6	35	6	47
Conflicting	—				6
Total	5	86	76	40	213

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap ESR1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

ESR1 · protein map & ClinVar variants

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

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Stage I Breast CancerStage II Breast CancerStage III Breast Cancer

Niraparib + Dostarlimab In BRCA Mutated Breast Cancer

ACTIVE NOT RECRUITING

NCT04584255Phase PHASE2Dana-Farber Cancer InstituteStarted 2020-12-18

NiraparibDostarlimab

Breast Cancer

Preoperative Fulvestrant With or Without Enzalutamide in ER+/Her2- Breast Cancer

ACTIVE NOT RECRUITING

NCT02955394Phase PHASE2University of Colorado, DenverStarted 2017-09-21

EnzalutamideFulvestrant

Bilateral Breast CarcinomaHER2-Negative Breast CarcinomaLocalized Breast Carcinoma

Testing the Addition of an Anti-cancer Drug, Berzosertib, to the Usual Treatment (Radiation Therapy) for Chemotherapy-Resistant Triple-Negative and Estrogen and/or Progesterone Receptor Positive, HER2 Negative Breast Cancer

ACTIVE NOT RECRUITING

NCT04052555Phase PHASE1National Cancer Institute (NCI)Started 2020-09-24

BerzosertibBiospecimen CollectionQuality-of-Life Assessment

ERα+ Breast CancerESR1 Gene Mutation

FES Imaging to Optimize Tamoxifen for Metastatic Breast Cancer

RECRUITING

NCT04174352Phase EARLY_PHASE1University of Wisconsin, MadisonStarted 2020-10-20

TamoxifenFES PET/CT

Advanced Breast Cancer

Saruparib (AZD5305) Plus Camizestrant Compared With CDK4/6 Inhibitor Plus Endocrine Therapy or Plus Camizestrant in HR-Positive, HER2-Negative (IHC 0, 1+, 2+/ ISH Non-amplified), BRCA1, BRCA2, or PALB2m Advanced Breast Cancer

RECRUITING

NCT06380751Phase PHASE3AstraZenecaStarted 2024-08-01

Saruparib (AZD5305)CamizestrantAbemaciclib

Central Nervous System (CNS) MetastasesBreast Cancer

A Phase II Observational Clinical Study on the Relationship Between Cerebrospinal Fluid Drug Concentration and Efficacy of Trastuzumab Deruxtecan in Central Nervous System Metastatic Breast Cancer

RECRUITING

NCT07653893Fudan UniversityStarted 2025-06-11

No Interventions

Primary Breast CancerRecurrent/Metastatic Breast Cancer

Breast Cancer Proteomics and Molecular Heterogeneity

RECRUITING

NCT01840293Cancer Trials IrelandStarted 2013-02

HER 2 Negative Breast Cancer

A Multicenter, Single-Arm, Phase II Exploratory Study of Eribulin in Combination With Anlotinib for HER2-Negative Recurrent/Metastatic Breast Cancer Previously Treated With Antibody-Drug Conjugates

RECRUITING

NCT07520760Phase PHASE2Sun Yat-sen UniversityStarted 2026-04-01

Eribulin in Combination with Anlotinib

Anatomic Stage I Breast Cancer AJCC v8Anatomic Stage IA Breast Cancer AJCC v8Anatomic Stage IB Breast Cancer AJCC v8

Genetic Testing in Predicting Tumor Response in Patients With Stage I-III HER2 Negative Invasive Breast Cancer

ACTIVE NOT RECRUITING

NCT01334021Phase PHASE2M.D. Anderson Cancer CenterStarted 2011-05-31

BiopsyConventional SurgeryGenetic Testing

Breast Cancer

Higher Per Daily Treatment-Dose Radiation Therapy or Standard Per Daily Treatment Radiation Therapy in Treating Patients With Early-Stage Breast Cancer That Was Removed by Surgery

ACTIVE NOT RECRUITING

NCT01349322Phase PHASE3Radiation Therapy Oncology GroupStarted 2011-05-24

Standard fractionation whole breast irradiationHypofractionated whole breast irradiationConcurrent boost

Pelvic Organ ProlapseFemale Urogenital Diseases

Pelvic Organs Prolapse Treatment Using Neodymium Laser

ACTIVE NOT RECRUITING

NCT05000957Phase NAMeLSyTech, LtdStarted 2021-10-03

Laser TreatmentBlood analysisСlinical urine test

Breast Cancer

PErsonalized TREatment of High-risk MAmmary Cancer - the PETREMAC Trial

ACTIVE NOT RECRUITING

NCT02624973Phase PHASE2Haukeland University HospitalStarted 2016-04-15