Variant classification summary

NM_001122740.1:c.1610A>G

ESR1 · NP_001116212.1:p.(Tyr537Cys) · NM_001122740.1

GRCh37: chr6:152419923 A>G · GRCh38: chr6:152098788 A>G

Gene: ESR1 Transcript: NM_001122740.1

Final call

VUS

PS3 supporting PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

ESR1

Transcript

NM_001122740.1

Protein

NP_001116212.1:p.(Tyr537Cys)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

PM2 (supporting): The variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada).

3

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.

4

PP3 (supporting): In silico analysis (REVEL score 0.922) supports a deleterious effect on protein function.

5

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.

6

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This 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.	pvs1_generic_framework
PS1	N/A	No 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.
PS2	N/A	No de novo observation data available for this variant in any source reviewed.
PS3	Met	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.	PMID:24185510 PMID:24398047 PMID:24185512
PS4	N/A	No 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.
PS5	N/A	No de novo observation data available for this variant.
PM1	Met	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.
PM2	Met	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).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not assessed	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.
PM6	N/A	No de novo observation data available for this variant.
PP1	N/A	No co-segregation data available for this variant.
PP2	N/A	ESR1 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.
PP3	Met	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.	revel bayesdel spliceai
PP4	N/A	No patient phenotype or family history information was provided for this case.
PP5	Not met	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.	oncokb
BA1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from all population databases. The allele frequency does not exceed the 0.3% threshold required for BS1.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	N/A	No observations in healthy adult individuals available. This variant has only been observed in tumor specimens and is absent from population databases.
BS3	Not met	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.	PMID:24185510 PMID:24398047 PMID:24185512
BS4	N/A	No segregation data available for this variant.
BP1	Not met	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.
BP2	N/A	No phasing data available. The variant has not been observed in trans or cis with any other pathogenic variant.
BP3	N/A	Skipped per instruction: variant is a missense substitution, not an in-frame deletion/insertion in a repetitive region.
BP4	Not met	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.	revel spliceai
BP5	N/A	No evidence of an alternate molecular basis for disease in cases harboring this variant.
BP6	Not met	No reputable source reports this variant as benign.
BP7	N/A	This is a missense variant (c.1610A>G, p.Tyr537Cys), not a synonymous variant. BP7 applies only to synonymous variants without predicted splice impact.

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