About ESR1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ESR1 c.1610A>G, p.(Tyr537Cys)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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
PS3Supporting
PS3 · supporting
Multiple independent in vitro functional studies demonstrate that p.Tyr537Cys confers constitutive, ligand-independent transcriptional activation of ESR1. Robinson et al. (2013) showed Y537C results in constitutive activity and continued hormone-independent growth. Jeselsohn et al. (2014) demonstrated ligand-independent activity relatively resistant to tamoxifen and fulvestrant in luciferase reporter assays in 293T cells. Toy et al. (2013) confirmed Y537C in multiple hormone-resistant breast cancer cohorts. All studies were performed in a somatic cancer context; evidence supports a damaging functional effect.
PM1Moderate
PM1 · moderate
The variant is located at codon 537 in the ligand-binding domain (LBD) of ESR1, a critical functional domain spanning the C-terminal region of the protein. Codon 537 lies within a statistically significant mutational hotspot (cancerhotspots.org) and is at the start of helix 12, a highly conserved region that undergoes conformational change upon ligand binding.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, consistent with PM2 (allele frequency < 0.1% in all populations).
PP3Supporting
PP3 · supporting
REVEL score of 0.922 strongly supports a deleterious effect on protein function. Multiple in silico predictors support pathogenicity. SpliceAI predicts no splice impact (max delta = 0.00), consistent with a protein-level effect.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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 supporting, PM1 moderate, PM2 supporting, PP3 supporting; combination = 1 moderate + 3 supporting, which maps to VUS.
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.
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: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
43 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52782924, n = 43 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.
27 criteria with recorded statuses: 4 met · 7 not met · 1 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PM1 (moderate): c.1610A>G (p.Tyr537Cys) is located in the ligand-binding domain of ESR1 at codon 537, a statistically significant mutational hotspot at the start of helix 12.
PM2 (supporting): The variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada).
PS3 (supporting): Multiple independent functional studies demonstrate that p.Tyr537Cys confers constitutive, ligand-independent transcriptional activation of ESR1, as shown in luciferase reporter assays and cell proliferation studies.
PP3 (supporting): In silico analysis (REVEL score 0.922) supports a deleterious effect on protein function.
PVS1 is not applicable: this is a missense variant outside canonical splice sites and not predicted to cause loss of function via a null mechanism.
Using ACMG/AMP 2015 generic combination rules (PMID:25741868), the evidence profile of 1 moderate (PM1) + 3 supporting (PM2, PS3, PP3) does not reach the threshold for Likely Pathogenic or Pathogenic classification. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 4
PS3 SupportingMultiple independent in vitro functional studies demonstrate that p.Tyr537Cys confers constitutive, ligand-independent transcriptional activation of ESR1. Robinson et al. (2013) showed Y537C results in constitutive activity and continued hormone-independent growth. Jeselsohn et al. (2014) demonstrated ligand-independent activity relatively resistant to tamoxifen and fulvestrant in luciferase reporter assays in 293T cells. Toy et al. (2013) confirmed Y537C in multiple hormone-resistant breast cancer cohorts. All studies were performed in a somatic cancer context; evidence supports a damaging functional effect. Details ▾Hide ▴
Evidence considered
- Luciferase reporter assay (293T cells) showing ligand-independent constitutive activation (PMID:24185510
- PMID:24398047).
- Hormone-independent transcriptional activity confirmed in multiple cell lines (PMID:24185512).
- Resistance to tamoxifen and fulvestrant demonstrated (PMID:24398047).
Still missing
- All functional studies are in a somatic cancer context
- no germline-specific functional data available.
Sources
PM1 ModerateThe variant is located at codon 537 in the ligand-binding domain (LBD) of ESR1, a critical functional domain spanning the C-terminal region of the protein. Codon 537 lies within a statistically significant mutational hotspot (cancerhotspots.org) and is at the start of helix 12, a highly conserved region that undergoes conformational change upon ligand binding. Details ▾Hide ▴
Evidence considered
- Variant lies within the ESR1 ligand-binding domain (LBD).
- Codon 537 is a statistically significant mutational hotspot.
- Located at the start of helix 12
- critical for ligand-dependent conformational change.
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, consistent with PM2 (allele frequency < 0.1% in all populations). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes).
- Absent from gnomAD-Canada v1.0 (genomes).
Sources
PP3 SupportingREVEL score of 0.922 strongly supports a deleterious effect on protein function. Multiple in silico predictors support pathogenicity. SpliceAI predicts no splice impact (max delta = 0.00), consistent with a protein-level effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.922 (strongly pathogenic prediction).
- BayesDel score: 0.381 (modest).
- SpliceAI max delta: 0.00 (no predicted splice impact).
Sources
Not met · 7 · evaluated, threshold not reached
PP5 No reputable source has reported this variant as pathogenic for a germline condition. OncoKB classifies the variant as Likely Oncogenic, which is a somatic oncogenicity classification and does not constitute a germline PP5 assertion. The ClinVar-linked PMIDs (22918138, 34131312) are general technical standards that do not mention this variant. Details ▾Hide ▴
Evidence considered
- OncoKB: Likely Oncogenic (somatic
- not germline). No germline pathogenic classification from any reputable source.
Sources
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency does not exceed the 1% threshold required for BA1. Details ▾Hide ▴
Evidence considered
- Variant is absent from all population databases.
Sources
BS1 This variant is absent from all population databases. The allele frequency does not exceed the 0.3% threshold required for BS1. Details ▾Hide ▴
Evidence considered
- Variant is absent from all population databases.
Sources
BS3 Well-established functional studies demonstrate that p.Tyr537Cys produces constitutive, ligand-independent activation of ESR1, a gain-of-function effect. These findings are inconsistent with BS3, which requires functional studies showing no damaging effect. Details ▾Hide ▴
Evidence considered
- Multiple independent studies demonstrate constitutive activation of ESR1 by p.Tyr537Cys.
Sources
BP1 ESR1 is not a gene in which primarily truncating variants cause disease. Known pathogenic variants in ESR1 are predominantly missense changes in the ligand-binding domain. Details ▾Hide ▴
Evidence considered
- ESR1 pathogenic variants are predominantly missense
- not truncating.
BP4 REVEL score of 0.922 strongly supports a deleterious effect on protein function, contradicting BP4 which requires multiple lines of computational evidence suggesting no impact. Details ▾Hide ▴
Evidence considered
- REVEL: 0.922 (damaging). SpliceAI: 0.00 (no splice impact).
Sources
revelspliceai ↗
BP6 No reputable source reports this variant as benign. Details ▾Hide ▴
Evidence considered
- No benign classification found in ClinVar or published literature.
Not assessed · 1 · no assessment recorded
PM5 The pm5 candidate harvesting pipeline could not confirm same-residue comparator variants with established germline pathogenic classifications. While p.Tyr537Asn (Y537N) and p.Tyr537Ser (Y537S) are well-characterized oncogenic variants at the same residue, none have been classified as pathogenic in a germline context in ClinVar. Details ▾Hide ▴
Evidence considered
- PM5 candidate pipeline returned 0 eligible comparators with germline pathogenic classifications.
Still missing
- No same-residue comparators with established germline pathogenic classification in ClinVar.
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.1610A>G, p.Tyr537Cys) that does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Details ▾Hide ▴
Evidence considered
- Missense substitution
- variant_bucket=other
- apply_generic_pvs1_framework=false.
Sources
PS1 N/ANo alternative nucleotide change at codon 537 producing p.Tyr537Cys has been independently classified as pathogenic. PS1 requires a different nucleotide substitution at the same codon resulting in the same amino acid change that is already established as pathogenic. Details ▾Hide ▴
Evidence considered
- Only c.1610A>G produces Y537C among observed nucleotide changes at this codon.
PS2 N/ANo de novo observation data available for this variant in any source reviewed. Details ▾Hide ▴
Still missing
- No parental testing data available.
PS4 N/ANo germline case-control data available. The variant has been observed exclusively in somatic tumor specimens (COSMIC n=43; multiple publications in metastatic breast cancer cohorts). These do not satisfy PS4 which requires statistically higher prevalence in affected individuals vs controls for a germline disorder. Details ▾Hide ▴
Evidence considered
- COSMIC: 43 somatic observations. All published observations are in tumor/neoplastic context.
Still missing
- No germline case-control or cohort data available.
PM6 N/ANo de novo observation data available for this variant. Details ▾Hide ▴
No further detail was recorded.
PP1 N/ANo co-segregation data available for this variant. Details ▾Hide ▴
Still missing
- No family studies available.
PP2 N/AESR1 is not established as a gene in which missense variants are a common mechanism of germline disease. The gene is predominantly associated with somatic (acquired) mutations in breast cancer. Details ▾Hide ▴
Evidence considered
- ESR1 germline disease mechanism is not well-established
- most pathogenic variants reported are somatic.
PP4 N/ANo patient phenotype or family history information was provided for this case. Details ▾Hide ▴
Still missing
- No clinical phenotype data provided.
BS2 N/ANo observations in healthy adult individuals available. This variant has only been observed in tumor specimens and is absent from population databases. Details ▾Hide ▴
Still missing
- No healthy adult carrier data.
BS4 N/ANo segregation data available for this variant. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP2 N/ANo phasing data available. The variant has not been observed in trans or cis with any other pathogenic variant. Details ▾Hide ▴
Still missing
- No phase information available.
BP3 N/ASkipped per instruction: variant is a missense substitution, not an in-frame deletion/insertion in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP5 N/ANo evidence of an alternate molecular basis for disease in cases harboring this variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is a missense variant (c.1610A>G, p.Tyr537Cys), not a synonymous variant. BP7 applies only to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 537.
PS5 N/ANo de novo observation data available for this variant. Details ▾Hide ▴
Still missing
- No parental testing data available.
Identifiers
- Gene
- ESR1
- Transcript
- NM_001122740.1
- Coding (HGVS c.)
- NM_001122740.1:c.1610A>G
- Protein (HGVS p.)
- NP_001116212.1:p.(Tyr537Cys)
- GRCh38
- chr6:152098788 A>G
- GRCh37
- chr6:152419923 A>G
- ClinVar
- 3764845, 3257896
- COSMIC
- COSV52782924
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
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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
- 0.922
- BayesDel
- 0.381
How the predictions were used
PP3 SupportingREVEL score of 0.922 strongly supports a deleterious effect on protein function. Multiple in silico predictors support pathogenicity. SpliceAI predicts no splice impact (max delta = 0.00), consistent with a protein-level effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.922 (strongly pathogenic prediction).
- BayesDel score: 0.381 (modest).
- SpliceAI max delta: 0.00 (no predicted splice impact).
Sources
BP4 REVEL score of 0.922 strongly supports a deleterious effect on protein function, contradicting BP4 which requires multiple lines of computational evidence suggesting no impact. Details ▾Hide ▴
Evidence considered
- REVEL: 0.922 (damaging). SpliceAI: 0.00 (no splice impact).
Sources
revelspliceai ↗
BP7 N/AThis is a missense variant (c.1610A>G, p.Tyr537Cys), not a synonymous variant. BP7 applies only to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 537.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.922. BayesDel score = 0.380621.
7 paper records listed. 3 cited in the classification.
Cited in the classification
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PMID 24185510 ↗Activating ESR1 mutations in hormone-resistant metastatic breast cancer.Robinson DR et al. · 2013 Decp.Tyr537Cys (Y537C) identified as one of five novel LBD-localized ESR1 mutations in hormone-resistant metastatic breast cancer. Constitutive, ligand-independent transcriptional activation demonstrated in luciferase reporter assays. Y537C shown to result in continued hormone-independent growth.→ PS3 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
Location Results; Table 1; Figure 2
Context Luciferase reporter assay, MCF7 and 293T cell lines
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PMID 24185512 ↗ESR1 ligand-binding domain mutations in hormone-resistant breast cancer.Toy W et al. · 2013 Decp.Tyr537Cys (Y537C) identified in hormone-resistant breast cancer cohorts. Found in both primary and metastatic tumor samples. The variant lies in the ligand-binding domain at the start of helix 12. Molecular dynamics simulations showed that mutations at codon 537 stabilize the agonist conformation of ERα.→ PS3 Names this variant
Source detail
p.Tyr537Cys Y537C 0.75 3.0 LBD/AF-2
Location Table 1, Table 2, Results paragraphs 2-3
Context Tumor sequencing cohorts; molecular dynamics simulations; cell line models (MCF7, endometrial)
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PMID 24398047 ↗Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer.p.Tyr537Cys (Y537C) detected at nucleotide level (c.1610A>C) in metastatic breast cancer samples. Luciferase reporter assays in 293T cells demonstrated ligand-independent transcriptional activity for Y537C, with partial resistance to tamoxifen and fulvestrant. Y537C was found in 11% of LBD-mutated cases in the EM+ cohort.→ PS3 Names this variant
Source detail
the Y537N, Y537C and D538G mutations lead to ligand independent activity that is relatively resistant to tamoxifen and fulvestrant
Location Table 1, Results paragraphs 3-5, Figure 1
Context Luciferase reporter assay, HEK293T cells; site-directed mutagenesis of ESR1 LBD
Other recorded publications
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PMID 9500442 ↗Ligand-independent activation of the estrogen receptors alpha and beta by mutations of a conserved tyrosine can be abolished by antiestrogens.Reports ligand-independent activation of ERα and ERβ by mutations of a conserved tyrosine at position 537. Examines p.Tyr537Asn (asparagine), not p.Tyr537Cys (cysteine). Demonstrates that Y537N mutation confers hormone-independent activation that can be abolished by antiestrogens.Does not name this variant
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PMID 35101336 ↗Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC).Horak P et al. · 2022Joint recommendations from ClinGen, CGC, and VICC for standards in classification of somatic variants in cancer. Does not discuss NM_001122740.1:c.1610A>G or p.Tyr537Cys.Does not name this variant
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PMID 22918138 ↗Opportunities and challenges associated with clinical diagnostic genome sequencing: a report of the Association for Molecular Pathology.Schrijver I et al. · 2012AMP report on opportunities and challenges of clinical diagnostic genome sequencing. Discusses general principles of NGS in constitutional and cancer testing. Does not mention NM_001122740.1:c.1610A>G, p.Tyr537Cys, or any specific ESR1 variant.Does not name this variant
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PMID 34131312 ↗Chromosomal microarray analysis, including constitutional and neoplastic disease applications, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).Shao L et al. · 2021ACMG technical standard for chromosomal microarray analysis in constitutional and neoplastic disorders. Does not discuss NM_001122740.1:c.1610A>G, p.Tyr537Cys, or any specific ESR1 variant.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/3257896/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/6-152419923-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr6-152098788-A-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/6-152098788-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001122740.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/ESR1/Y537C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=162563613
- 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 = 3257896)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.922. BayesDel score = 0.380621.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52782924, n = 43 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.