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…

Primary Disease Associations & Inheritance

{Migraine, susceptibility to}MIM #157300

{Myocardial infarction, susceptibility to}MIM #608446

Breast cancer, somaticMIM #114480

Estrogen resistanceMIM #615363

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Breast cancer, somatic; Estrogen resistance; no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

1542

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.19

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in ESR1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

657 rare PASS variants

Rare truncating (LoF)

1 in 5,200

45 rare PASS variants

Rare synonymous (reference)

1 in 91

336 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ESR1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 4,300
South Asian	~43k	1 in 92	≈ 1 in 21,000
Remaining (unassigned)	~30k	1 in 73	1 in 920
European (Finnish)	~27k	1 in 440	≈ 1 in 13,000
Admixed American	~22k	1 in 66	≈ 1 in 20,000
African / African American	~21k	1 in 75	1 in 3,600
East Asian	~20k	1 in 120	≈ 1 in 4,000
Ashkenazi Jewish	~13k	1 in 180	≈ 1 in 3,000
Middle Eastern	~2,884	1 in 70	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 7 of 8 coding exons well covered in gnomAD exomes; exon 3 marginal. Genomes: all 8.? see exons ↓

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

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 2021-01-21

NiraparibDostarlimab

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

Breast AdenocarcinomaHormone Receptor PositiveStage IA Breast Cancer AJCC v7

Hormone Therapy With or Without Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Negative Breast Cancer (The TAILORx Trial)

ACTIVE NOT RECRUITING

NCT00310180Phase PHASE3National Cancer Institute (NCI)Started 2006-04-07

AnastrozoleExemestaneLaboratory Biomarker Analysis

Estrogen-receptor-positive Breast CancerMetastatic Breast CancerBreast Cancer

PhII Randomized CAPecitabine + ELAcestrant vs. Capecitabine Alone in ER+ Breast Cancer (CAPELA)

RECRUITING

NCT07222215Phase PHASE2Kristina A. FanucciStarted 2026-01-16

CapecitabineElacestrant

Advanced Breast CancerER-positive Breast CancerHER2-negative Breast Cancer

Elacestrant + Everolimus in Patients ER+/HER2-, ESR1mut, Advanced Breast Cancer Progressing to ET and CDK4/6i.

RECRUITING

NCT06382948Phase PHASE3MedSIRStarted 2024-12-05

EverolimusElacestrantPlacebo

Metastatic Breast Cancer

Patient-Centric Study to Assess the Impact of Genomic Profiling on the Treatment of Patients With Metastatic Breast Cancer in Spain

RECRUITING

NCT06991946SOLTI Breast Cancer Research GroupStarted 2025-05-20

Liquid BiopsyArchival Tumor DNA

ESR1 Gene MutationAdvanced Breast Cancer

Current Status of Treatment for Chinese Patients With ESR1-mutated HR+/HER2-advanced Breast Cancer

RECRUITING

NCT06548919SciClone PharmaceuticalsStarted 2024-08-08

Endocrine therapyChemotherapy Prednisone

Breast AdenocarcinomaEstrogen Receptor NegativeHER2/Neu Negative

Doxorubicin Hydrochloride and Cyclophosphamide Followed by Paclitaxel With or Without Carboplatin in Treating Patients With Triple-Negative Breast Cancer

ACTIVE NOT RECRUITING

NCT02488967Phase PHASE3NRG OncologyStarted 2015-07-26

CarboplatinCyclophosphamideDoxorubicin Hydrochloride

Ductal Breast Carcinoma in Situ

Surgical Excision vs Neoadjuvant Radiotherapy+Delayed Surgical Excision of Ductal Carcinoma

RECRUITING

NCT03909282Phase NAStanford UniversityStarted 2019-03-22

LumpectomyPartial breast irradiation prior to surgery

Breast CancerInvasive Breast CancerCarcinoma in Situ of the Breast

Prospective Breast Cancer Biospecimen Collection

RECRUITING

NCT04074720Thomas Jefferson UniversityStarted 2018-05-10