ESR1 c.1610A>C, p.Tyr537Ser

Reasoning

PS3 is met at strong strength. The exact ESR1 p.Tyr537Ser variant (NM_000125.4:c.1610A>C) was tested in multiple independent functional systems with wild-type comparators and hormone/antiestrogen controls. In HEK293T ERE-luciferase assays, Y537S showed strong constitutive transcriptional activation without estradiol and two- to fourfold higher 4-hydroxytamoxifen and fulvestrant IC50 values than wild type (PMID:24185510). In SKBR3 cells, activity was approximately 60-fold above wild type without estradiol; the result was reproduced across additional breast and endometrial cell lines, with increased ER-target gene expression in MCF7 cells and hormone-independent tumor growth in xenografts (PMID:24185512). Independent biophysical work showed hormone-independent SRC3 coactivator recruitment by Y537S, with Kd 13.6 +/- 2.0 nM versus no detectable apo recruitment for wild-type ERalpha, and reduced ligand binding (PMID:26836308). The exact Y537S construct was also characterized in recombinant-receptor binding and dissociation assays, although those results alone were not damaging (PMID:11914066). The concordant cellular, transcriptional, in vivo, structural, and biophysical results establish a reproducible damaging gain-of-function effect relevant to ESR1 biology.

Rule

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

Evidence considered

• PMID:24185510, Results paragraph on the HEK293T ERE-luciferase assay: the exact p.Tyr537Ser mutant had strong constitutive ERE reporter activation without beta-estradiol; 4-hydroxytamoxifen and fulvestrant IC50 values were two- to fourfold higher than wild-type ESR1.
• PMID:24185512, Results and Figures 2-5: in ER-negative SKBR3 cells, Y537S ERE-luciferase activity was 60X wild-type levels without estradiol; the mutant increased ER-target transcripts, promoted growth after estrogen withdrawal in MCF7 xenografts, and retained greater residual activity under antiestrogen treatment.
• PMID:26836308, Results and Tables 1-2: purified Y537S ERalpha recruited SRC3 without estradiol with Kd 13.6 +/- 2.0 nM, while wild-type ERalpha showed no apo coactivator recruitment; structural and binding studies supported constitutive activation and reduced antagonist effectiveness.
• PMID:11914066, Tables 1-2 and molecular-modeling results: recombinant Y537S ESR1 was directly tested in estradiol-binding and dissociation assays, providing an orthogonal characterization of the exact substitution, but not a benign functional conclusion.
• Assay controls and biological relevance: studies used wild-type ESR1 comparators, estradiol-depleted conditions, estradiol stimulation, antiestrogen dose-response testing, reporter normalization, ER-target transcriptional readouts, and breast-cancer cellular or xenograft models.

Sources

Reasoning

PM2 is met at supporting strength. NM_000125.4:c.1610A>C (p.Tyr537Ser) is absent from gnomAD v2.1 and gnomAD v4.1. It is also reported absent from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes. The observed allele frequency is therefore 0, meeting the supplied generic PM2 supporting threshold of <=0.0001.

Rule

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.

Evidence considered

• gnomAD v2.1 exome record for 6-152419923-A-C: absent; allele frequency 0.
• gnomAD v4.1 record for chr6-152098788-A-C: absent; allele frequency 0.
• The evidence record also reports absence from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes.
• The supplied generic PM2 supporting calibration is <=0.0001, identified in the prompt as the ClinGen SVI 2020 recommendation (PMID:25741868).

Sources

Reasoning

NM_000125.4:c.1610A>C produces the missense consequence NP_000116.2:p.(Tyr537Ser) in exon 8, so the generic missense path applies: REVEL only. REVEL is 0.911, which reaches the supplied PP3 moderate threshold of >= 0.773 but not the strong threshold of >= 0.932. The SpliceAI max delta of 0.004 and BayesDel score of 0.418913 were not used: SpliceAI is not evidence for a missense PP3 decision, and no generic ACMG-strength calibration is established for BayesDel.

Rule

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant. ... PP3 (moderate): >= 0.773 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)

Evidence considered

• Variant consequence: NM_000125.4:c.1610A>C, NP_000116.2:p.(Tyr537Ser), missense in exon 8; the generic missense REVEL path therefore applies and SpliceAI is not used.
• Local REVEL lookup: score 0.911.
• Generic ClinGen SVI REVEL calibration supplied in the governing case instructions: PP3 moderate requires >=0.773 and PP3 strong requires >=0.932; the calibration is attributed to Pejaver et al. 2022, PMID:36413997.
• BayesDel score 0.418913 was not used because no generic ACMG-strength calibration is established for BayesDel.

Sources

Reasoning

The governing PS4 rule requires a significantly increased prevalence in affected individuals compared with controls and states that RR or OR must be >5.0 with a confidence interval excluding 1.0. The reviewed variant-specific literature reports affected cancer cohorts, including p.Tyr537Ser in 3 patients in PMID:24185510, p.Tyr537Ser among 14 ESR1-mutant cases in an 80-case cohort in PMID:24185512, and 13 of 95 metastatic breast-cancer patients with somatic ESR1 mutations in PMID:27986707, but none supplies unaffected or population-control counts matched to the case cohort, an OR/RR, or a confidence interval. The two literature-pass PS4 leads, PMID:22918138 and PMID:34131312, were verified from their abstracts as general diagnostic/genome-testing standards and do not report this variant in a case-control study. Therefore no case-control enrichment estimate can be computed and PS4 is not met; no prevalence comparison reaches the required OR/RR >5.0 with CI excluding 1.0.

Rule

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.

Evidence considered

• PMID:24185510: the exact p.Tyr537Ser alteration was observed in three patients in a six-patient ER-positive metastatic breast-cancer sequencing cohort; the report provides no unaffected or population-control comparison.
• PMID:24185512: ESR1 ligand-binding-domain mutations were identified in 14 of 80 metastatic ER-positive breast tumors, including p.Tyr537Ser; this is a case series/cohort without a matched control frequency or OR/RR.
• PMID:27986707: Y537S was reported in 13 of 95 metastatic breast-cancer patients with somatic ESR1 mutations; the cited result is not a case-control comparison and has no control count or confidence interval.
• PMID:22918138 and PMID:34131312 were the literature-pass PS4 leads; their available abstracts describe general molecular-testing standards, not variant-specific case-control prevalence evidence. These PMIDs are not present as source_registry keys, so they are not placed in evidence_refs.

Still missing

• A matched case-control study or equivalent control-frequency data for ESR1 p.Tyr537Ser is not available.
• No OR/RR and 95% confidence interval can be calculated from the available reports.

Sources

Reasoning

The governing PP5 rule concerns a reputable source reporting the variant as pathogenic when the underlying evidence is unavailable for independent evaluation. The exact ClinVar record for NM_000125.4:c.1610A>C (p.Tyr537Ser) has one single-submitter, one-star somatic classification of Oncogenic, with no expert-panel submission and no validated submission-level pathogenic or likely-pathogenic assertion. The available literature reports functional and somatic observations but does not provide a qualifying reputable pathogenic assertion of the type required here. PP5 is therefore not met.

Rule

Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.

Evidence considered

• ClinVar variation 3257895 exactly matches NM_000125.4:c.1610A>C (p.Tyr537Ser), but the record has one submission, one-star criteria-provided single-submitter status, somatic origin, and classification Oncogenic rather than an expert-panel Pathogenic or Likely pathogenic assertion.
• The ClinVar submission audit reports zero expert-panel submissions and zero usable criterion-lead submissions.

Sources

Reasoning

BA1 is not met. NM_000125.4:c.1610A>C (p.Tyr537Ser) was absent from gnomAD v2.1 and gnomAD v4.1, with no allele frequency approaching the generic stand-alone threshold of >=0.05. The non-cancer gnomAD v2.1 exome and v3.1 genome subsets were also absent. No ancestry-specific elevated frequency was identified.

Rule

Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.

Evidence considered

• gnomAD v2.1 exome record for 6-152419923-A-C: absent; allele frequency 0.
• gnomAD v4.1 record for chr6-152098788-A-C: absent; allele frequency 0.
• The evidence record also reports absence from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes.
• The supplied generic BA1 calibration is >=0.05, ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868).

Sources

Reasoning

BS1 is not met. The variant was absent from gnomAD v2.1 and v4.1 and therefore does not exceed the supplied generic default BS1 threshold of >=0.01. No ancestry-specific frequency elevation, founder effect, prevalence estimate, penetrance estimate, or allelic-heterogeneity calculation indicates that this variant is more frequent than expected for a disorder. Because no elevated frequency was observed, the reduced-penetrance/late-onset exception does not alter the conclusion.

Rule

Allele frequency is greater than expected for the disorder.

Evidence considered

• gnomAD v2.1 exome record for 6-152419923-A-C: absent; allele frequency 0.
• gnomAD v4.1 record for chr6-152098788-A-C: absent; allele frequency 0.
• The evidence record also reports absence from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes.
• The supplied generic BS1 calibration is >=0.01; the prompt identifies Whiffin et al. 2017 (PMID:28518168) as the preferred per-gene maximum-credible-frequency framework when an elevated frequency requires interpretation.

Sources

Reasoning

BS3 is not met. The available functional evidence does not show no damaging effect on ESR1 function or splicing; instead, multiple controlled studies of the exact p.Tyr537Ser substitution demonstrate constitutive estrogen-independent transcription, increased ER-target gene expression, hormone-independent tumor growth, antiestrogen resistance, and hormone-independent coactivator recruitment. PMID:11914066 found near-wild-type estradiol affinity in one binding assay, but that isolated result does not establish absence of damage and does not outweigh the concordant damaging functional findings in independent cellular, in vivo, and biophysical assays.

Rule

Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.

Evidence considered

• PMID:24185510, HEK293T ERE-luciferase and antiestrogen dose-response assays: Y537S was constitutively active without estradiol and had higher antiestrogen IC50 values than wild type.
• PMID:24185512, SKBR3, MCF7, and xenograft experiments: Y537S produced approximately 60X wild-type basal reporter activity, increased ER-target transcription, and supported estrogen-independent tumor growth.
• PMID:26836308, purified ERalpha biophysical and structural assays: Y537S recruited SRC3 without hormone and altered ligand-binding and agonist/antagonist conformational behavior.
• PMID:11914066, recombinant-receptor binding assays: Y537S retained similar estradiol affinity to wild type, but this single assay result does not demonstrate absence of damaging effect across ESR1 function and does not evaluate splicing.

Sources

Reasoning

NM_000125.4:c.1610A>C produces the missense consequence NP_000116.2:p.(Tyr537Ser), so BP4 must be evaluated on the generic missense REVEL path only. REVEL is 0.911, which is above the supplied BP4 supporting cutoff of <= 0.29 and therefore does not support no impact. The SpliceAI max delta of 0.004 was not substituted because a splice prediction cannot establish BP4 for a missense amino-acid substitution; BayesDel was not used because no generic ACMG-strength calibration is established.

Rule

Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)

Evidence considered

• Variant consequence: NM_000125.4:c.1610A>C, NP_000116.2:p.(Tyr537Ser), missense in exon 8; the generic missense REVEL path applies and SpliceAI is not used.
• Local REVEL lookup: score 0.911.
• Generic ClinGen SVI REVEL calibration supplied in the governing case instructions: BP4 supporting requires <=0.29; the calibration is attributed to Pejaver et al. 2022, PMID:36413997.
• BayesDel score 0.418913 was not used because no generic ACMG-strength calibration is established for BayesDel.

Sources

Reasoning

The governing BP5 rule requires the variant to be found in a case with an alternate molecular basis for disease. The available evidence documents ESR1 p.Tyr537Ser in somatic breast-cancer cohorts and functional models, but does not document a specific case in which an independent alternate molecular cause explains the disease while this variant is present. BP5 is not met.

Rule

Variant found in a case with an alternate molecular basis for disease.

Evidence considered

• The reviewed ESR1 literature reports somatic p.Tyr537Ser observations and functional studies, not a case with a separately established alternate molecular basis for disease.

Still missing

• No case-level alternate pathogenic molecular diagnosis is reported.

Reasoning

The governing BP6 rule concerns a reputable source reporting the variant as benign when the evidence is unavailable for independent evaluation. The exact ClinVar record is a single-submitter one-star somatic Oncogenic record, not an expert-panel Benign or Likely benign classification, and no qualifying benign reputable-source assertion is present. BP6 is not met.

Rule

Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.

Evidence considered

• ClinVar variation 3257895 exactly matches NM_000125.4:c.1610A>C (p.Tyr537Ser), but its one submission is classified Oncogenic with one-star single-submitter status, not Benign or Likely benign.
• The ClinVar submission audit reports zero expert-panel submissions.

Sources

Reasoning

The queried variant is ESR1 p.Tyr537Ser (NM_000125.4:c.1610A>C). The reviewed literature reports this exact amino-acid change, but the available records establish somatic oncogenic or functional observations rather than a previously established pathogenic classification suitable for the generic PS1 comparator requirement. Therefore, the evidence does not establish a qualifying previously pathogenic variant for PS1.

Rule

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

Evidence considered

• PMID:24185510 reports p.Tyr537Ser in three metastatic breast-cancer tumors and functional activation, but this is a somatic observation and not a qualifying generic ACMG pathogenic comparator.
• PMID:24185512 reports recurrent p.Tyr537Ser in metastatic ER-positive breast cancer and functional activity, without establishing a germline or generic ACMG pathogenic classification.
• ClinVar variation 3257895 is classified Oncogenic with a single somatic submitter and one-star review status; this does not document a previously established pathogenic variant for generic PS1.

Still missing

• A previously established pathogenic variant record for the same amino-acid change, with an applicable disease context, is not documented.

Sources

Reasoning

The available evidence concerns somatic ESR1 p.Tyr537Ser observations in metastatic breast-cancer tumors and provides no germline proband record, no confirmed maternity and paternity, and no documented absence of family history. Therefore, the required de novo evidence for PS2 cannot be assessed.

Rule

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.

Evidence considered

• The available variant-specific literature reports p.Tyr537Ser in metastatic breast-cancer tumors, including tumor-versus-matched-normal sequencing, rather than a germline trio or parental testing.
• No case evidence documents confirmed maternity, confirmed paternity, or absence of family history.

Still missing

• Germline testing of the proband is not documented.
• Maternity and paternity confirmation is not documented.
• Family-history information is not documented.

Sources

Reasoning

ESR1 p.Tyr537Ser lies in the ligand-binding domain, and the literature describes recurrent mutations at Tyr537 and functional importance of this region. However, generic PM1 requires a mutational hotspot and/or critical, well-established functional domain without benign variation. The available evidence does not establish absence of benign variation across the relevant ligand-binding domain, and the cancer-hotspot result is a somatic hotspot record rather than a generic ACMG route that can substitute for the missing domain-level benign-variation evidence. Thus PM1 cannot be assessed as met from the available evidence.

Rule

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

Evidence considered

• PMID:24185510 places p.Tyr537Ser among ESR1 ligand-binding-domain mutations and reports the variant in metastatic tumors with functional activation.
• PMID:24185512 describes recurrent ESR1 ligand-binding-domain mutations including Tyr537Ser and functional activity of the variant.
• PMID:27986707 reports recurrent somatic mutations at Tyr537, including Y537S, Y537C, and Y537N, supporting residue-level recurrence but not domain-wide absence of benign variation.
• The Cancer Hotspots record reports ESR1 Y537 as a statistically significant somatic hotspot, but the generic rule's required no-benign-variation condition is not resolved by that record.

Still missing

• A documented critical-domain or hotspot assessment demonstrating no benign variation across the applicable ESR1 region is needed.

Sources

Reasoning

PM3 cannot be assessed because the available evidence concerns somatic ESR1 p.Tyr537Ser observations in metastatic breast tumors and provides no recessive-disease context, pathogenic allele in trans, or parent/offspring phase testing. The study reports tumor sequencing relative to matched normal DNA and transcriptome corroboration, but does not establish allelic phase with another pathogenic variant.

Rule

PM3: For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.

Evidence considered

• PMID:24185510 reports p.Tyr537Ser in metastatic breast-cancer tumors using tumor whole-exome sequencing relative to matched normal DNA and transcriptome corroboration; it provides no report of a pathogenic second allele or phase testing.
• The available case evidence is somatic oncology evidence and does not establish a recessive ESR1 disease model for applying PM3.

Still missing

• A defined recessive ESR1 disorder context is not available.
• No pathogenic second allele is reported.
• No parent, offspring, or other valid phase testing is reported.

Sources

Reasoning

The reviewed evidence identifies alternate missense substitutions at Tyr537, including Y537C and Y537N, but does not establish either alternate as a previously determined pathogenic missense variant under the generic ACMG/AMP framework. Somatic recurrence and functional activity alone do not satisfy the required pathogenic comparator. Therefore PM5 is not assessed.

Rule

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

Evidence considered

• PMID:27986707 reports alternate somatic Tyr537 substitutions Y537C and Y537N alongside Y537S, but does not provide a qualifying pathogenic classification for those comparators.
• PMID:24185512 reports recurrent Tyr537Ser and other ESR1 ligand-binding-domain mutations, but the available extraction does not establish a different pathogenic missense comparator at the same residue.

Still missing

• A different missense variant at Tyr537 with an established pathogenic classification is not documented.

Sources

Reasoning

The available evidence concerns somatic ESR1 p.Tyr537Ser observations in metastatic breast-cancer tumors and provides no germline proband record or evidence that the variant arose de novo without parental testing. PM6 therefore cannot be assessed.

Rule

Assumed de novo, but without confirmation of paternity and maternity.

Evidence considered

• The available variant-specific literature reports tumor-associated ESR1 p.Tyr537Ser in metastatic breast cancer and does not report a germline de novo observation or parental testing.
• No case evidence documents that the variant was assumed de novo.

Still missing

• Germline testing of the proband is not documented.
• A de novo observation is not documented.
• Parental testing status is not documented.

Sources

Reasoning

The available case evidence documents ESR1 somatic gain-of-function mutations and absence of this variant from gnomAD, but it does not establish both requirements for generic PP2: a low rate of benign missense variation for the gene and missense variation as a common disease mechanism in the applicable disease context. The individual variant's population absence and functional or oncogenic reports cannot substitute for those gene-level prerequisites.

Rule

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

Evidence considered

• gnomAD v2.1 and v4.1 report the queried variant as absent, which is variant-level evidence and does not quantify ESR1's benign missense rate.
• PMID:24185510 and PMID:24185512 describe recurrent somatic ESR1 activating mutations, but do not establish the generic PP2 gene-level requirements for the applicable disease context.

Still missing

• Gene-level evidence quantifying a low rate of benign missense variation is unavailable.
• Applicable disease-context evidence that missense variants are a common mechanism of disease is unavailable.

Sources

Reasoning

The governing PP4 rule requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The available case materials identify an ESR1 p.Tyr537Ser somatic cancer variant and literature context involving metastatic ER-positive breast cancer, but they do not provide a patient-level phenotype or family history demonstrating a highly specific single-gene disorder. The criterion therefore cannot be assessed from the available clinical phenotype information.

Rule

Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.

Evidence considered

• The case summary identifies a somatic ESR1 p.Tyr537Ser variant and metastatic ER-positive breast-cancer literature context, but does not provide the patient's detailed phenotype or family history.

Still missing

• Patient-level phenotype and family-history details are not available.
• A disease context with a demonstrably single genetic etiology is not established for this somatic ESR1 finding.

Reasoning

BS2 was not assessed. The available population records show the variant is absent from gnomAD v2.1, gnomAD v4.1, and the reported non-cancer subsets, but they do not provide a verified healthy-adult observation, zygosity, inheritance mode, disease prevalence, or penetrance assessment for ESR1-related disease. Absence from population databases cannot establish or exclude the specific BS2 healthy-adult observation requirement.

Rule

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.

Evidence considered

• gnomAD v2.1 and v4.1 report the variant as absent; these records do not document a healthy-adult carrier or zygosity.
• The evidence record also reports absence from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes; these results likewise do not establish the BS2 observation requirement.

Still missing

• A verified observation of this variant in a healthy adult with documented zygosity and relevant inheritance model.
• A defined ESR1-related disorder with expected full penetrance at an early age.

Sources

Reasoning

No affected family members were evaluated for the variant, and no familial genotypes or phenotypes are available. Consequently, lack of segregation cannot be determined and BS4 is not assessed.

Rule

Lack of segregation in affected members of a family.

Evidence considered

• The case contains no affected-family segregation data or non-segregation observations.

Still missing

• No family pedigree is documented.
• No affected-relative testing is documented.
• No familial genotype-phenotype comparison is documented.

Reasoning

The available evidence does not establish that ESR1 disease is caused primarily by truncating variants, nor does it provide a validated gene-disease spectrum showing missense variants are generally not the disease mechanism. The reports in this case concern somatic ESR1 missense gain-of-function mutations and cannot establish the generic BP1 gene-level premise.

Rule

Missense variant in a gene for which primarily truncating variants are known to cause disease.

Evidence considered

• PMID:24185510 and PMID:24185512 report somatic ESR1 missense activating mutations in metastatic breast cancer, but do not establish that the relevant disease is primarily caused by truncating variants.

Still missing

• A validated gene-disease variant spectrum demonstrating that ESR1 disease is caused primarily by truncating variants is unavailable.

Sources

Reasoning

BP2 cannot be assessed because no affected-proband or family observation documents NM_000125.4:c.1610A>C in trans with a pathogenic variant or in cis with a pathogenic variant. The available literature reports somatic tumor observations and functional studies, not constitutional cis/trans phase relationships.

Rule

BP2: Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.

Evidence considered

• PMID:24185510 reports the variant in somatic metastatic breast-cancer tumors and does not report constitutional cis/trans phase with another pathogenic variant.
• No available case source documents the queried variant in an affected proband with a pathogenic allele in trans or cis.

Still missing

• No affected-proband or family genotype is reported with a second pathogenic variant.
• No cis/trans phase result is available.
• No evidence establishes a fully penetrant dominant ESR1 disorder for the BP2 trans pathway.

Sources