VCV001263746.6 - ClinVar

NM_000125.4(ESR1):c.1782G>A (p.Thr594=)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Benign/Likely benign

2 out of 4 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000125.4(ESR1):c.1782G>A (p.Thr594=)

Variation ID: 1263746 Accession: VCV001263746.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6q25.1 6: 152098960 (GRCh38) [ NCBI UCSC ] 6: 152420095 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 8, 2024	Mar 23, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000125.4:c.1782G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000116.2:p.Thr594=	synonymous
NM_001122740.2:c.1782G>A	NP_001116212.1:p.Thr594=	synonymous
NM_001122741.2:c.1782G>A	NP_001116213.1:p.Thr594=	synonymous
NM_001122742.2:c.1782G>A	NP_001116214.1:p.Thr594=	synonymous
NM_001291230.2:c.1788G>A	NP_001278159.1:p.Thr596=	synonymous
NM_001291241.2:c.1779G>A	NP_001278170.1:p.Thr593=	synonymous
NM_001328100.2:c.851-26306G>A		intron variant
NM_001385568.1:c.1782G>A	NP_001372497.1:p.Thr594=	synonymous
NM_001385569.1:c.1782G>A	NP_001372498.1:p.Thr594=	synonymous
NM_001385570.1:c.*197G>A		3 prime UTR
NM_001385571.1:c.*197G>A		3 prime UTR
NM_001385572.1:c.*197G>A		3 prime UTR
NC_000006.12:g.152098960G>A
NC_000006.11:g.152420095G>A
NG_008493.2:g.447270G>A
LRG_992:g.447270G>A
LRG_992t1:c.1782G>A

... more HGVS ... less HGVS

Protein change

Other names

594G-A

Canonical SPDI

NC_000006.12:152098959:G:A

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.18870 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.17200

Trans-Omics for Precision Medicine (TOPMed) 0.18188

1000 Genomes Project 30x 0.18801

1000 Genomes Project 0.18870

Exome Aggregation Consortium (ExAC) 0.18928

The Genome Aggregation Database (gnomAD), exomes 0.19011

The Genome Aggregation Database (gnomAD), exomes 0.19368

The Genome Aggregation Database (gnomAD) 0.17850

The Genome Aggregation Database (gnomAD) 0.17968

Links

ClinGen: CA4052546 OMIM: 133430.0005 dbSNP: rs2228480 VarSome

Comment on variant

NCBI staff provided an HGVS expression for 133430.0005 based on this statement in the paper by Colson et al., 2004 (PubMed 15133719): 'occurs in codon 594 of exon 8 and consists of a guanine to adenine change at nucleotide 2014 (SNP rs2228480)'.

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ESR1		-	-	GRCh38 GRCh37	148	258

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Benign (1)	criteria provided, single submitter	Aug 17, 2018	RCV001674740.2
Migraine with or without aura, susceptibility to	risk factor (1)	no assertion criteria provided	Jun 1, 2004	RCV001843377.1
Estrogen resistance syndrome Familial cancer of breast Migraine with or without aura, susceptibility to, 1 Myocardial infarction, susceptibility to	Likely benign (1)	criteria provided, single submitter	Mar 23, 2022	RCV002506722.1
ESR1-related disorder	Benign (1)	no assertion criteria provided	Mar 11, 2019	RCV003975895.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Aug 17, 2018) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Not Provided	GeneDx Accession: SCV001890571.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: show This variant is associated with the following publications: (PMID: 15934440, 19636371, 19860576) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely benign (Mar 23, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Familial cancer of breast Migraine with or without aura, susceptibility to, 1 Myocardial infarction, susceptibility to Estrogen resistance syndrome	Fulgent Genetics, Fulgent Genetics Accession: SCV002796516.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

risk factor (Jun 01, 2004) N Not contributing to aggregate classification	no assertion criteria provided	MIGRAINE, SUSCEPTIBILITY TO	OMIM Accession: SCV000038338.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 15133719 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: Migraine (157300) is a painful and debilitating disorder with a significant genetic component. Steroid hormones, in particular estrogen, have long been considered to play a … (more) Migraine (157300) is a painful and debilitating disorder with a significant genetic component. Steroid hormones, in particular estrogen, have long been considered to play a role in migraine, as variations in hormone levels are associated with migraine onset in many individuals with the disorder. Steroid hormones mediate their activity via hormone receptors, which have a wide tissue distribution. Estrogen receptors have been localized to the brain in regions considered to be involved in migraine pathogenesis. Colson et al. (2004) examined the ESR1 gene for a potential role in migraine pathogenesis and susceptibility. A population-based cohort of 224 patients with migraine and 224 matched controls were genotyped for the 594G-A polymorphism located in exon 8 of the ESR1 gene. Statistical analysis indicated a significant difference between patients with migraine and those without migraine in both the allele frequencies (P = 0.003) and genotype distributions (P = 0.008). An independent follow-up study using this marker in an additional population-based cohort of 260 patients with migraine and 260 matched controls resulted in a significant association between the 2 groups with regard to allele frequencies and genotype distributions. The findings supported the hypothesis that genetic variation in hormone receptors, in particular the ESR1 gene, may play a role in migraines. (less)

Benign (Mar 11, 2019) N Not contributing to aggregate classification	no assertion criteria provided	ESR1-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004799231.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: show This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The estrogen receptor 1 G594A polymorphism is associated with migraine susceptibility in two independent case/control groups.	Colson NJ	Neurogenetics	2004	PMID: 15133719

Text-mined citations for rs2228480 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated May 17, 2025