rs2234693

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is The variant received -4 classification points (ACGS-UK Somatic Oncogenicity v2025): 0P and 4B. B1_Strong

The NM_000125.4(ESR1):c.453-397T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The gene ESR1 is a tumor suppressor gene (CancerMine: 23 TSG, 33 oncogene, 32 driver citations). The gene ESR1 is a known oncogene (CancerMine: 23 TSG, 33 oncogene, 32 driver citations). The gene ESR1 is a cancer driver gene (CancerMine: 23 TSG, 33 oncogene, 32 driver citations). The variant allele was found at a cumulative frequency of 0.465 (AC=70,725) in the gnomAD database across 152,008 control chromosomes, including 16,806 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.532. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review stars).

Frequency

Genomes: 𝑓 0.47 ( 16806 hom., cov: 32)

Consequence

ESR1
NM_000125.4 intron

Scores

Clinical Significance

risk factor no assertion criteria provided O:1

Conservation

PhyloP100: 1.18

Publications

608 publications found

Variant links:

Genes affected

ESR1 (HGNC:3467): (estrogen receptor 1) 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]

ESR1 Gene-Disease associations (from GenCC):

estrogen resistance syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, PanelApp Australia

ESR1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000125.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 points.

GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.532 — exceeds 1% threshold (B1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000125.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ESR1	NM_000125.4	MANE Select	c.453-397T>C	intron	N/A	NP_000116.2	P03372-1
ESR1	NM_001291230.2		c.453-397T>C	intron	N/A	NP_001278159.1
ESR1	NM_001122740.2		c.453-397T>C	intron	N/A	NP_001116212.1	P03372-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ESR1	ENST00000206249.8	TSL:1 MANE Select	c.453-397T>C	intron	N/A	ENSP00000206249.3	P03372-1
ESR1	ENST00000406599.5	TSL:1	c.452+33836T>C	intron	N/A	ENSP00000384064.1	Q9H2M1
ESR1	ENST00000427531.6	TSL:1	c.-67-397T>C	intron	N/A	ENSP00000394721.2	P03372-4

Frequencies

GnomAD3 genomes

AF:

0.465

AC:

70661

AN:

151890

Hom.:

16789

Cov.:

show subpopulations

Gnomad AFR

AF:

0.538

Gnomad AMI

AF:

0.510

Gnomad AMR

AF:

0.365

Gnomad ASJ

AF:

0.457

Gnomad EAS

AF:

0.396

Gnomad SAS

AF:

0.432

Gnomad FIN

AF:

0.397

Gnomad MID

AF:

0.452

Gnomad NFE

AF:

0.462

Gnomad OTH

AF:

0.443

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.465

AC:

70725

AN:

152008

Hom.:

16806

Cov.:

AF XY:

0.458

AC XY:

34033

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.538

AC:

22314

AN:

41444

American (AMR)

AF:

0.365

AC:

5572

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.457

AC:

1586

AN:

3470

East Asian (EAS)

AF:

0.395

AC:

2043

AN:

5166

South Asian (SAS)

AF:

0.430

AC:

2071

AN:

4814

European-Finnish (FIN)

AF:

0.397

AC:

4189

AN:

10560

Middle Eastern (MID)

AF:

0.442

AC:

129

AN:

292

European-Non Finnish (NFE)

AF:

0.462

AC:

31416

AN:

67968

Other (OTH)

AF:

0.445

AC:

940

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1924

3848

5771

7695

9619

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

640

1280

1920

2560

3200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.461

Hom.:

32226

Bravo

AF:

0.462

Asia WGS

AF:

0.422

AC:

1465

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.429

AC:

52685

AN:

122742

Turkish Variome

AF:

0.468

AC:

724

AN:

1546

Hom.:

168

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.412

AC:

3690

AN:

8960

Hom.:

758

ABraOM SABE-WGS-1171

AF:

0.445

AC:

1043

AN:

2342

Hom.:

220

ClinVar

ClinVar submissions

Significance:risk factor

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Myocardial infarction, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.3

(source)

DANN

Benign

0.68

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACGS-UK Somatic Oncogenicity v2025

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over