Variant classification summary

NM_000125.4:c.1610A>C

ESR1 · NP_000116.2:p.(Tyr537Ser) · NM_000125.4

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

Gene: ESR1 Transcript: NM_000125.4

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP3 moderate

Variant details

Gene

ESR1

Transcript

NM_000125.4

Protein

NP_000116.2:p.(Tyr537Ser)

gnomAD AF

ClinVar

Oncogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic evidence: PS3 strong reflects reproducible constitutive ESR1 activation and antiestrogen resistance in independent functional systems.

2

Pathogenic evidence: PM2 supporting reflects absence from gnomAD v2.1 and v4.1, with allele frequency 0.

3

Pathogenic evidence: PP3 moderate reflects a REVEL score of 0.911 above the 0.773 threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong pathogenic criterion plus one moderate-or-supporting pathogenic criterion supports Likely Pathogenic; PS3 strong and PM2 supporting satisfy this rule, with PP3 moderate also applied.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: exact p.Tyr537Ser reports are available, but no qualifying previously established pathogenic classification is documented for the generic PS1 comparator.	PMID:24185510 PMID:24185512 clinvar
PS2	Not assessed	Not assessed: no germline proband, confirmed maternity and paternity, or documented absence of family history is available for this somatic tumor variant.	PMID:24185510 PMID:24185512
PS3	Met	Met, strong: Y537S showed approximately 60-fold estrogen-independent ER activity versus wild type, with concordant cellular, xenograft, and biophysical evidence across independent studies.	PMID:24185510 PMID:24185512 PMID:26836308 PMID:11914066
PS4	Not met	Not met: affected-cohort reports lack unaffected or population-control counts, OR/RR, and a confidence interval required to establish PS4 enrichment.	PMID:24185510 PMID:24185512 PMID:27986707
PM1	Not assessed	Not assessed: Tyr537 is in the ESR1 ligand-binding domain, but domain-wide absence of benign variation required by generic PM1 is not established.	PMID:24185510 PMID:24185512 PMID:27986707 hotspots
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, giving allele frequency 0 versus the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: tumor reports provide no pathogenic variant in trans or parent/offspring phase testing needed to evaluate PM3.	PMID:24185510
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: alternate Tyr537 substitutions are reported, but none is documented as a previously determined pathogenic missense comparator.	PMID:27986707 PMID:24185512
PM6	Not assessed	Not assessed: no germline proband evidence or observation of a de novo variant without parental testing is documented.	PMID:24185510 PMID:24185512
PP1	N/A	Not applicable: no inherited disease pedigree or affected-family segregation is available, and the evidence concerns somatic metastatic breast-cancer tumors.	PMID:24185510 PMID:24185512
PP2	Not assessed	Not assessed: gene-level low benign-missense rate and common missense disease mechanism are not established together for generic PP2.	gnomad_v2 gnomad_v4 PMID:24185510 PMID:24185512
PP3	Met	Met at moderate strength: missense REVEL score 0.911 exceeds the PP3 moderate threshold of 0.773.	revel
PP4	Not assessed	Not assessed: no patient-level phenotype or family history is provided to show a highly specific disease with a single genetic etiology.
PP5	Not met	Not met: ClinVar has only a single-submitter one-star Oncogenic label, not an exact-variant expert-panel Pathogenic or Likely pathogenic classification.	clinvar
BA1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, far below the generic BA1 allele-frequency threshold of 5%.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 show no alternate alleles, below the generic BS1 default threshold of 1%.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no verified healthy adult carrying the variant, zygosity, inheritance model, and full early-age penetrance information are available.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: independent assays show constitutive ER activation and antiestrogen resistance, so the evidence does not demonstrate no damaging effect on ESR1 function or splicing.	PMID:24185510 PMID:24185512 PMID:26836308 PMID:11914066
BS4	Not assessed	Not assessed: no affected relatives, familial genotypes, or segregation observations are available to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: primarily truncating ESR1 disease causation is not established, so the generic BP1 gene-level premise remains unresolved.	PMID:24185510 PMID:24185512
BP2	Not assessed	Not assessed: no constitutional cis or trans phase observation with a pathogenic variant is reported for this variant.	PMID:24185510
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL score 0.911 is above the BP4 supporting cutoff of 0.29.	revel
BP5	Not met	Not met: no documented case shows this variant alongside an independent alternate molecular basis explaining the disease.
BP6	Not met	Not met: no exact-variant expert-panel Benign or Likely benign assertion is present; ClinVar instead reports a single-submitter Oncogenic label.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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