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).1 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.2 PP3 (supporting): In silico analysis (REVEL score 0.922) supports a deleterious effect on protein function.3 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.4 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).5
ESR1
Final classification
VUS
ESR1 c.1610A>G · p.Tyr537Cys
ESR1
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.
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.
Classification rationale
PS3PM1PM2PP3
VUS
ESR1 c.1610A>G
PS3 + PM1 + PM2 + PP3
→
VUS
3
revel
5
generic_acmg_combination_rules
Gene diagram
· NM_001122740.1 · variants mapped to exon structure
ESR1
NM_001122740.1
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Likely Oncogenic
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
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52782924, n = 43 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 4 further PMIDs triaged but not cited — see Sources & References.
Activating ESR1 mutations in hormone-resistant metastatic breast cancer.
Searched
c.1610A>Gp.Tyr537CysY537CTyr537537Cys
Found
p.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.
Variant
✓ Names this variant — characterised directly
Applied to
→PS3 supports · met
Why
Variant-specific functional data confirmed constitutive activation; referenced in PS3 assessment at supporting strength.
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 · full text
ESR1 ligand-binding domain mutations in hormone-resistant breast cancer.
Searched
p.Tyr537CysY537CTyr537537Cc.1610
Found
p.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.
Variant
✓ Names this variant — characterised directly
Applied to
→PS3 supports · met
Why
Variant-specific data in tumor cohorts confirmed; functional characterization through structural modeling supports damaging effect. Referenced in PS3 assessment at supporting strength.
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) · full text
Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer.
Searched
c.1610A>Gc.1610A>Cp.Tyr537CysY537C1610537CysTyr537
Found
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.
Variant
✓ Names this variant — characterised directly
Applied to
→PS3 supports · met
Why
Variant-specific functional data with nucleotide-level confirmation (c.1610A>C); referenced in PS3 assessment at supporting strength.
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 · full text
Sources & reference links
Triaged references · 4 PMIDs not cited in assessment
9500442 ↗
Ligand-independent activation of the estrogen receptors alpha and beta by mutations of a conserved tyrosine can be abolished by antiestrogens.
ONCOKB
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).
CLINVAR
22918138 ↗
Opportunities and challenges associated with clinical diagnostic genome sequencing: a report of the Association for Molecular Pathology.
CLINVAR
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).
CLINVAR