About ESR1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ESR1 c.1613A>G, p.(Asp538Gly)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Strong
PS3 · strong
Well-established functional studies from multiple independent research groups consistently demonstrate that p.Asp538Gly (D538G) confers constitutive, ligand-independent transcriptional activity of ESR1, promotes coactivator recruitment in the absence of estrogen, and confers resistance to antiestrogen therapies. Evidence includes luciferase reporter assays in MCF-7, MDA-MB-231, and HEK293T cells (PMIDs: 24185510, 24185512, 24217577), X-ray crystallography and hydrogen-deuterium exchange mass spectrometry demonstrating stabilized agonist conformation of helix 12 (PMID: 26836308), co-immunoprecipitation showing constitutive SRC-1 binding (PMID: 24217577), and CRISPR/Cas9-engineered heterozygous D538G endometrial cancer cell models (PMID: 31362937). The functional data are replicated across five independent laboratories and multiple orthogonal assays. Caveat: all functional evidence derives from somatic cancer studies; germline-specific functional data are not available.
PM1Moderate
PM1 · moderate
p.Asp538 is located in helix 12 of the ESR1 ligand-binding domain (LBD), a critical functional domain governing receptor activation and coactivator recruitment. The residue lies within a statistically significant mutational hotspot (cancerhotspots.org). Multiple structural studies confirm that D538G alters the conformation of helix 12, and the residue is part of a well-characterized cluster of gain-of-function somatic mutations (Y537S, Y537N, Y537C, D538G) that constitutively activate ESR1.
PM2Moderate
PM2 · moderate
This variant is absent from all population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes). Under non-VCEP generic ACMG guidance, PM2 is applied when allele frequency is below 0.1% in population databases.
PP3Supporting
PP3 · supporting
The REVEL meta-predictor score of 0.914 strongly supports a deleterious effect. SpliceAI predicts no splicing impact (max delta score = 0.00). BayesDel score of 0.346 is below typical pathogenicity thresholds. While BayesDel does not reach the damaging threshold, REVEL (which integrates multiple individual predictors including conservation, evolutionary, and protein-level features) strongly supports a deleterious effect, satisfying PP3 at supporting level.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PM1 moderate, PM2 moderate, PP3 supporting; combination = 1 strong + 2 moderate + 1 supporting, which maps to Likely Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded. ClinVar API review status: criteria provided, single submitter.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
162 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52781024, n = 162 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 4 met · 7 not met · 2 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001122740.1:c.1613A>G (p.Asp538Gly) in ESR1 is a missense variant in exon 9 encoding a substitution in helix 12 of the ligand-binding domain.
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, satisfying PM2 (moderate).
The variant is located at a statistically significant mutational hotspot within helix 12 of the ESR1 ligand-binding domain, a critical functional domain, satisfying PM1 (moderate).
Multiple independent functional studies demonstrate that p.Asp538Gly confers constitutive, ligand-independent transcriptional activity, promotes coactivator recruitment in the absence of estrogen, and confers resistance to antiestrogen therapies. Evidence includes luciferase reporter assays, co-immunoprecipitation, X-ray crystallography, HDX-MS, and cell proliferation assays across multiple laboratories, satisfying PS3 (strong).
The REVEL meta-predictor score of 0.914 supports a deleterious effect, satisfying PP3 (supporting).
Caveat: all functional evidence derives from somatic cancer studies of acquired endocrine resistance; no germline-specific functional or clinical evidence is available. The variant has not been reported as a germline pathogenic variant. Classification should be interpreted with the understanding that this variant's clinical significance in a germline context is uncertain.
PVS1 is not applicable as this is a missense variant. PS1, PS2, PS4, PS5, PM5, PM6, PP1, PP4, PP5, BA1, BS1, BS2, BS3, BS4, BP1, BP2, BP4, BP5, BP6, and BP7 are not met or not applicable.
No criteria match.
Met · 4
PS3 StrongWell-established functional studies from multiple independent research groups consistently demonstrate that p.Asp538Gly (D538G) confers constitutive, ligand-independent transcriptional activity of ESR1, promotes coactivator recruitment in the absence of estrogen, and confers resistance to antiestrogen therapies. Evidence includes luciferase reporter assays in MCF-7, MDA-MB-231, and HEK293T cells (PMIDs: 24185510, 24185512, 24217577), X-ray crystallography and hydrogen-deuterium exchange mass spectrometry demonstrating stabilized agonist conformation of helix 12 (PMID: 26836308), co-immunoprecipitation showing constitutive SRC-1 binding (PMID: 24217577), and CRISPR/Cas9-engineered heterozygous D538G endometrial cancer cell models (PMID: 31362937). The functional data are replicated across five independent laboratories and multiple orthogonal assays. Caveat: all functional evidence derives from somatic cancer studies; germline-specific functional data are not available. Details ▾Hide ▴
Evidence considered
- Constitutive ligand-independent transcriptional activity in luciferase reporter assays (MCF-7
- MDA-MB-231
- HEK293T cells).
- Ligand-independent coactivator (SRC-1/SRC3) recruitment demonstrated by co-IP and tr-FRET.
- X-ray crystallography showing D538G stabilizes agonist conformation of helix 12.
- HDX-MS confirming altered conformational dynamics favoring coactivator binding.
- Reduced affinity for tamoxifen (Ki ~10-fold higher vs WT) and estradiol (Kd ~5-fold higher).
- Enhanced proliferation and antiestrogen resistance in breast cancer cell lines.
- CRISPR/Cas9-engineered heterozygous D538G endometrial cancer cell model (PMID:31362937).
Still missing
- All functional evidence is from somatic cancer contexts
- no germline-specific functional assays exist.
Sources
PM1 Moderatep.Asp538 is located in helix 12 of the ESR1 ligand-binding domain (LBD), a critical functional domain governing receptor activation and coactivator recruitment. The residue lies within a statistically significant mutational hotspot (cancerhotspots.org). Multiple structural studies confirm that D538G alters the conformation of helix 12, and the residue is part of a well-characterized cluster of gain-of-function somatic mutations (Y537S, Y537N, Y537C, D538G) that constitutively activate ESR1. Details ▾Hide ▴
Evidence considered
- Located in helix 12 of the ligand-binding domain
- a critical functional domain.
- Statistically significant hotspot residue per cancerhotspots.org (external database
- not in source_registry).
- Structural studies confirm D538 is essential for ligand-dependent regulation of AF-2 cleft.
Sources
PM2 ModerateThis variant is absent from all population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes). Under non-VCEP generic ACMG guidance, PM2 is applied when allele frequency is below 0.1% in population databases. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- Absent from gnomAD-Canada v1.0.
Still missing
- Absence may reflect somatic-only origin rather than germline constraint.
Sources
PP3 SupportingThe REVEL meta-predictor score of 0.914 strongly supports a deleterious effect. SpliceAI predicts no splicing impact (max delta score = 0.00). BayesDel score of 0.346 is below typical pathogenicity thresholds. While BayesDel does not reach the damaging threshold, REVEL (which integrates multiple individual predictors including conservation, evolutionary, and protein-level features) strongly supports a deleterious effect, satisfying PP3 at supporting level. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.914 (strongly damaging).
- BayesDel score: 0.346 (below typical threshold of 0.5).
- SpliceAI max delta score: 0.00 (no splicing impact).
Still missing
- HCI prior not available for ESR1.
Sources
Not met · 7 · evaluated, threshold not reached
PS1 No prior germline pathogenic or likely pathogenic classification exists for p.Asp538Gly in ClinVar or the literature. The ClinVar entry (VariationID 3764845) is classified as 'Oncogenic' in a somatic context only, which does not satisfy the PS1 requirement for a germline pathogenic assertion at the same amino acid change. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 3764845 is classified as 'Oncogenic' (somatic context) by a single submitter. No germline P/LP classification exists.
Still missing
- No germline pathogenic classification for this residue change.
Sources
PS4 No germline case-control data are available. The variant has been observed 162 times in COSMIC (somatic cancers), but these are tumor-acquired mutations and do not constitute germline case-control prevalence evidence for PS4. Details ▾Hide ▴
Evidence considered
- COSMIC COSV52781024
- n=162 somatic observations. No germline case-control prevalence data. (COSMIC data not in source_registry — external database.)
Still missing
- No germline case-control or cohort prevalence studies.
PP5 No reputable source has reported this variant as germline pathogenic or likely pathogenic. The ClinVar entry (VariationID 3764845) is classified as 'Oncogenic' in the somatic context only, which does not constitute a germline pathogenic assertion for PP5. Details ▾Hide ▴
Evidence considered
- ClinVar classification is 'Oncogenic' (somatic)
- not P/LP in germline context.
Still missing
- No germline P/LP assertion from any reputable clinical laboratory or database.
Sources
BA1 The variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada). Under non-VCEP generic ACMG guidance, BA1 requires an allele frequency >1%. The observed frequency of 0% does not meet this threshold. Details ▾Hide ▴
Evidence considered
- Allele frequency = 0 in gnomAD v2.1
- v4.1
- and gnomAD-Canada.
Sources
BS1 The variant is absent from all population databases. Under non-VCEP generic ACMG guidance, BS1 requires an allele frequency >0.3%. The observed frequency of 0% does not meet this threshold. Details ▾Hide ▴
Evidence considered
- Allele frequency = 0 in gnomAD v2.1
- v4.1
- and gnomAD-Canada.
Sources
BS3 Multiple well-established functional studies (see PS3) demonstrate that p.Asp538Gly is a gain-of-function mutation conferring constitutive ligand-independent transcriptional activity and antiestrogen resistance. These studies do not show a benign or neutral effect; rather, they consistently demonstrate a damaging functional alteration. Details ▾Hide ▴
Evidence considered
- Functional studies consistently demonstrate gain-of-function
- not benign effect.
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. The REVEL meta-predictor score of 0.914 strongly supports a deleterious effect, contradicting BP4. SpliceAI is neutral (max delta = 0.00). BP4 is not satisfied because the strongest computational evidence points toward pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL 0.914 strongly supports deleterious effect
- BP4 is contradicted.
Sources
Not assessed · 2 · no assessment recorded
PP2 PP2 requires gene-specific calibration (low rate of benign missense variation where missense variants are a common disease mechanism). No CSPEC/VCEP framework or HCI prior score is available for ESR1 to establish whether PP2 applies in a germline context. The variant is a well-established gain-of-function somatic mutation, but germline missense constraint data are absent. Details ▾Hide ▴
Evidence considered
- No CSPEC/VCEP framework or HCI prior data for ESR1. Gene not in standard PP2 gene lists.
Still missing
- Gene-specific missense constraint calibration not available for ESR1 in germline context.
PP4 No patient phenotype or clinical history is available for the proband. PP4 requires evaluation of whether the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Without clinical data, this criterion cannot be assessed. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data available for the proband.
Still missing
- Patient phenotype and family history data are needed to assess PP4.
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense substitution (NM_001122740.1:c.1613A>G; p.Asp538Gly). PVS1 requires a null variant (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, or exon deletion). This variant does not fall into any PVS1 null-variant bucket per the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant
- variant_bucket='other'
- apply_generic_pvs1_framework=false.
Sources
PS2 N/ANo de novo data are available for this variant. All documented occurrences are in somatic tumor samples (metastatic breast and endometrial cancers), not in germline de novo contexts. Details ▾Hide ▴
Evidence considered
- No de novo observation data in any reviewed source.
PM5 N/AThe pm5_candidates automated assessment was unable to confirm classic same-residue PM5 semantics. No comparator missense variants at residue 538 with a confirmed germline pathogenic classification were identified for PM5 evaluation. Details ▾Hide ▴
Evidence considered
- pm5_candidates.json: eligible_for_classic_pm5_search=false
- no same-residue comparator variants with germline P/LP classification.
Sources
pm5_candidates
PM6 N/ANo de novo observation data are available for this variant. All documented occurrences are somatic, acquired mutations in tumor tissue. Details ▾Hide ▴
Evidence considered
- No de novo data in any reviewed source.
PP1 N/ANo family segregation data are available. This variant has only been documented as a somatic, acquired mutation in tumor samples, not in family-based germline studies. Details ▾Hide ▴
Evidence considered
- No cosegregation or family data in any source.
BS2 N/ANo data are available regarding observation of this variant in healthy adult individuals for a fully penetrant dominant disorder. The variant is absent from gnomAD and has only been observed as a somatic mutation in tumor tissue. Details ▾Hide ▴
Evidence considered
- No observation in healthy adult controls.
BS4 N/ANo family segregation data are available. This variant has only been documented as a somatic acquired mutation; no germline family studies exist. Details ▾Hide ▴
Evidence considered
- No family segregation data to evaluate lack of cosegregation.
BP1 N/ABP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. No CSPEC/VCEP framework defines BP1 for ESR1. The ESR1 germline disease mechanism is not established as exclusively truncating; regulatory variants and missense mutations may also contribute to disease predisposition per the available literature. Details ▾Hide ▴
Evidence considered
- No CSPEC/VCEP framework defines BP1 for ESR1. Disease mechanism not established as truncating-only.
BP2 N/ANo data are available regarding observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- No trans-configuration data available.
BP5 N/ANo data are available regarding observation of this variant in a case with an alternate molecular basis for disease. No proband clinical data or genetic workup results are available. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available.
BP6 N/ANo reputable source has reported this variant as benign. BP6 cannot be applied without a benign assertion from a trusted source. Details ▾Hide ▴
Evidence considered
- No benign classification from any source.
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact. This is a missense variant (p.Asp538Gly), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
PS5 N/APS5 is not a defined criterion in the generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868). This criterion does not exist in the standard ACMG/AMP classification schema. Details ▾Hide ▴
Evidence considered
- PS5 is not part of the ACMG/AMP 2015 classification criteria set.
Sources
generic_acmg_combination_rules
Identifiers
- Gene
- ESR1
- Transcript
- NM_001122740.1
- Coding (HGVS c.)
- NM_001122740.1:c.1613A>G
- Protein (HGVS p.)
- NP_001116212.1:p.(Asp538Gly)
- GRCh38
- chr6:152098791 A>G
- GRCh37
- chr6:152419926 A>G
- ClinVar
- 3764845
- COSMIC
- COSV52781024
Gene diagram
Every interpreted variant in ESR1, mapped onto the exon structure of NM_001122740.1. Select a row to find it on the plot.
ESR1NM_001122740.1
Fetching transcript structure from UCSC…
Exons
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Transcript span
—
Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in ESR1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.914
- BayesDel
- 0.346
How the predictions were used
PP3 SupportingThe REVEL meta-predictor score of 0.914 strongly supports a deleterious effect. SpliceAI predicts no splicing impact (max delta score = 0.00). BayesDel score of 0.346 is below typical pathogenicity thresholds. While BayesDel does not reach the damaging threshold, REVEL (which integrates multiple individual predictors including conservation, evolutionary, and protein-level features) strongly supports a deleterious effect, satisfying PP3 at supporting level. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.914 (strongly damaging).
- BayesDel score: 0.346 (below typical threshold of 0.5).
- SpliceAI max delta score: 0.00 (no splicing impact).
Still missing
- HCI prior not available for ESR1.
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. The REVEL meta-predictor score of 0.914 strongly supports a deleterious effect, contradicting BP4. SpliceAI is neutral (max delta = 0.00). BP4 is not satisfied because the strongest computational evidence points toward pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL 0.914 strongly supports deleterious effect
- BP4 is contradicted.
Sources
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact. This is a missense variant (p.Asp538Gly), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.914. BayesDel score = 0.345967.
7 paper records listed. 6 cited in the classification.
Cited in the classification
-
PMID 24185510 ↗Activating ESR1 mutations in hormone-resistant metastatic breast cancer.Robinson DR et al. · 2013 DecRobinson et al. identified ESR1 ligand-binding domain mutations including p.Asp538Gly in 6 of 11 patients with ER-positive metastatic breast cancer previously treated with anti-estrogen therapies. Functional characterization in HEK293T cells demonstrated that ESR1-D538G confers constitutive ligand-independent transcriptional activity.→ PS3 → PM1 Names this variant
Source detail
The five new LBD-localized ESR1 mutations identified here (encoding p.Leu536Gln, p.Tyr537Ser, p.Tyr537Cys, p.Tyr537Asn and p.Asp538Gly) were shown to result in constitutive activity and continued responsiveness to anti-estrogen therapies in vitro.
Location Abstract; Results (index patient MO_1051 and MO_1167); Figure 3 (functional assays)
Context Luciferase reporter assays with estrogen response element (ERE) reporter in HEK293T cells; whole-exome and transcriptome sequencing of metastatic breast cancer samples.
-
PMID 24185512 ↗ESR1 ligand-binding domain mutations in hormone-resistant breast cancer.Toy W et al. · 2013 DecToy et al. identified ESR1 LBD mutations including p.Asp538Gly in 5 of 44 (11%) metastatic ER-positive breast tumors after prolonged hormonal treatment. Functional assays in multiple cell lines demonstrated that Asp538Gly confers estrogen-independent receptor activation (approximately 15-fold above wild-type basal levels) and reduced sensitivity to tamoxifen and fulvestrant.→ PS3 → PM1 Names this variant
Source detail
Asp538Gly (15X WT levels) ... the already high levels driven by the Tyr537Ser (1.4X basal Tyr537Ser level), Asp538Gly (1.5X basal Asp538Gly level), and Ser463Pro/Asp538Gly (1.6X basal Ser463Pro/Asp538Gly level) mutants.
Location Results; Figure 2 (luciferase reporter assays); Supplementary Table 2
Context ERE-luciferase reporter assays in MCF-7, T47D, ZR75-1, MDA-MB-231, and Ishikawa cell lines; targeted sequencing of 230 cancer genes (MSKCC panel).
-
PMID 24217577 ↗D538G mutation in estrogen receptor-α: A novel mechanism for acquired endocrine resistance in breast cancer.Merenbakh-Lamin et al. identified the D538G ESR1 mutation (c.1613A>G) in liver metastases of 5 of 13 patients with ER-positive metastatic breast cancer who developed endocrine resistance. The mutation was absent in matched primary tumors obtained prior to treatment. Structural modeling and luciferase reporter assays demonstrated that D538G induces a conformational change in helix 12 enabling ligand-independent coactivator binding and constitutive transcriptional activity. The mutant conferred tamoxifen resistance and enhanced proliferation in MCF-7 cells.→ PS3 → PM1 Names this variant
Source detail
a mutation of A to G at position 1,613 of ERα, resulting in a substitution of aspartic acid at position 538 to glycine (D538G), was identified in liver metastases.
Location Abstract lines 57-66; Results 'Identification of D538G mutation' (line 263-278); Figure 1 (structural modeling); Figure 2 (luciferase assays); Table 1 (clinical characteristics)
Context ERE-luciferase reporter assays in MCF-7 and MDA-MB-231 cells; co-immunoprecipitation for SRC-1 binding; structural modeling with Rosetta; molecular docking; MTT proliferation assays; Foundation One clinical sequencing panel.
-
PMID 24398047 ↗Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer.Jeselsohn et al. identified ESR1 LBD mutations including D538G in 9 of 76 (12%) ER-positive metastatic breast tumor specimens, with D538G representing 33% of detected mutations. The mutation was detected in metastatic samples but absent in matched untreated primary tumors. Site-directed mutagenesis was used to generate the D538G construct for functional studies, and the mutation was confirmed to confer constitutive activity.→ PS3 → PM1 Names this variant
Source detail
The specific mutations include: Y537N (33%), D538G (33%), Y537S (22%) and Y537C (11%).
Location Results; Methods (site-directed mutagenesis primers for D538G)
Context Targeted sequencing of ER+ metastatic tumors; site-directed mutagenesis using GeneArt system; matched primary-metastatic pair analysis.
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PMID 26836308 ↗Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation.Fanning et al. performed comprehensive biophysical and structural characterization of the D538G ESR1 mutation. X-ray crystallography (1.90 Å resolution), hydrogen-deuterium exchange mass spectrometry (HDX-MS), and tr-FRET coactivator binding assays demonstrated that D538G stabilizes the agonist conformation of helix 12, enabling constitutive SRC3 coactivator recruitment in the absence of hormone. The D538G mutant showed reduced estradiol binding affinity (Kd = 1.30 ± 0.63 nM vs WT 0.26 ± 0.13 nM) and approximately 10-fold reduced tamoxifen affinity (Ki = 3.42 ± 0.50 nM vs WT 0.337 ± 0.018 nM).→ PS3 → PM1 Names this variant
Source detail
the Y537S and D538G mutations elevate the basal or constitutive activity of ERα and confer resistance to the beneficial effects of the SERM, SERD, and AI therapies.
Location Abstract; Results (tr-FRET coactivator binding, radioligand binding assays, proteolytic susceptibility, HDX-MS, X-ray crystallography); Figures 1-5; Tables 1-3
Context tr-FRET coactivator binding assays with purified ERα LBD and SRC3 NRD; radioligand binding assays with 3H-E2; trypsin proteolysis assays; HDX-MS; X-ray crystallography (D538G-E2 complex at 1.90 Å); molecular dynamics simulations.
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PMID 31362937 ↗Estrogen-independent molecular actions of mutant estrogen receptor 1 in endometrial cancer.Blanchard Z et al. · 2019 SepBlanchard et al. generated CRISPR/Cas9-engineered Ishikawa endometrial cancer cell lines heterozygous for the D538G ESR1 LBD mutation. The study demonstrated that D538G-mutant endometrial cancer cells exhibit estrogen-independent genomic binding and transcriptional activity distinct from wild-type ESR1, extending functional characterization of this variant to the endometrial cancer context.→ PS3 Names this variant
Source detail
we created endometrial cancer cells that are heterozygous for the D538G ESR1 ligand binding domain mutation (or wild-type ESR1 for controls) coupled with a FLAG epitope tag.
Location Abstract; Results 'Generation of D538G ESR1 mutant and wild-type cell lines'; Figure 1
Context CRISPR/Cas9-mediated epitope tagging in Ishikawa endometrial cancer cells; ChIP-seq; RNA-seq; western blot.
Other recorded publications
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PMID 29533785 ↗Systematic Functional Annotation of Somatic Mutations in Cancer.Ng PK et al. · 2018Ng et al. describe a moderate-throughput functional genomic platform for systematic annotation of somatic mutations in cancer. The study screens mutations across multiple cancer genes using viability assays and functional proteomic profiling. NM_001122740.1:c.1613A>G (p.Asp538Gly) was not identified in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/3764845/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/6-152419926-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr6-152098791-A-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/6-152098791-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001122740.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/ESR1/D538G
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=162562718
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 3764845)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.914. BayesDel score = 0.345967.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52781024, n = 162 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.