LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-05
Case ID: NM_000125.4_c.1613A_G_20261105_081750
Framework: ACMG/AMP 2015
Variant classification summary

NM_000125.4:c.1613A>G

ESR1  · NP_000116.2:p.(Asp538Gly)  · NM_000125.4
GRCh37: chr6:152419926 A>G  ·  GRCh38: chr6:152098791 A>G
Gene: ESR1 Transcript: NM_000125.4
Final call
Likely Pathogenic
PS3 strong PM2 supporting PP3 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
ESR1
Transcript
NM_000125.4
Protein
NP_000116.2:p.(Asp538Gly)
gnomAD AF
ClinVar
Oncogenic
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Pathogenic: PS3 strong is met by replicated functional evidence of constitutive ESR1 activation and endocrine resistance.
2
Likely Pathogenic: PM2 supporting is met because the variant is absent from gnomAD v2.1 and v4.1.
3
Likely Pathogenic: PP3 supporting is met because REVEL is 0.914, above the generic threshold of 0.644.
Final determination: Under the generic ACMG/AMP fallback, one strong pathogenic criterion plus two supporting pathogenic criteria supports a Likely Pathogenic classification.
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: D538G is repeatedly reported and functionally active, but no reviewed source provides a prior explicitly established pathogenic classification for the same amino-acid change.
PMID:24185510 PMID:24185512 PMID:24217577 PMID:24398047 PMID:26836308 clinvar
PS2 Not assessed Not assessed: no germline proband-level de novo result, confirmed maternity and paternity, or documented absence of family history is available.
PMID:24398047
PS3 Met Met, strong: D538G showed ligand-independent ESR1 activity, including SRC3 binding at Kd 151 +/- 20 nM versus no detectable wild-type binding.
PMID:24185510 PMID:24185512 PMID:24217577 PMID:24398047 PMID:26836308
PS4 Not met Not met: exact D538G was 3/76 versus 0/115 controls, with corrected OR 11.00 but 95% CI 0.56-216.06 including 1.0.
PMID:24398047
PM1 Not assessed Not assessed: D538 is in a functional ligand-binding domain, but domain-wide absence of benign variation is not established under the generic PM1 rule.
PMID:24185510 PMID:24185512 PMID:26836308 hotspots gnomad_v2 gnomad_v4
PM2 Met Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, meeting the <=0.0001 PM2 threshold.
gnomad_v2 gnomad_v4
PM3 N/A Not applicable: no recessive ESR1 disorder or germline trans observation is established; available reports are somatic tumor studies without parent or offspring phase testing.
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: no different pathogenic missense substitution at ESR1 residue 538 is documented in the reviewed evidence.
pm5_candidates PMID:24185510 PMID:24185512 PMID:24217577 PMID:24398047 PMID:26836308
PM6 Not assessed Not assessed: no germline proband with an assumed de novo variant or documented parental testing is available.
PMID:24398047
PP1 Not assessed Not assessed: no affected relatives, informative meioses, or genotype-phenotype segregation data are reported for this variant.
PMID:24398047
PP2 Not assessed Not assessed: recurrent ESR1 missense mutations are reported, but the required low benign-missense rate and disease-mechanism evidence are not quantified.
oncokb PMID:24185510 PMID:24185512 PMID:24398047 gnomad_v2 gnomad_v4
PP3 Met Met at supporting strength: REVEL 0.914 meets the generic PP3 supporting threshold of >=0.644 but not the moderate threshold of >=0.773.
revel
PP4 Not met Not met: metastatic ER-positive breast cancer and endocrine resistance are nonspecific phenotypes with multiple molecular causes, not a single-etiology disease signature.
PMID:24217577 PMID:24398047
PP5 Not met Not met: ClinVar lists exact D538G as single-submitter Oncogenic, not an expert-panel Pathogenic or Likely pathogenic classification.
clinvar
BA1 Not met Not met: the variant is absent from gnomAD v2.1 and v4.1, far below the generic BA1 threshold of >=0.05.
gnomad_v2 gnomad_v4 clinvar
BS1 Not met Not met: the variant is absent from gnomAD, so no filtering FAF exceeds the generic BS1 default of 0.01.
gnomad_v2 gnomad_v4 PMID:24185510 PMID:24185512 PMID:24217577 PMID:24398047 PMID:26836308
BS2 Not assessed Not assessed: no healthy adult carrying the variant was documented, and the reported homozygous observation was confined to a metastatic tumor.
gnomad_v2 gnomad_v4 PMID:24398047
BS3 Not met Not met: all five reviewed studies reported damaging functional effects, including constitutive ESR1 activity and endocrine resistance for exact D538G.
PMID:24185510 PMID:24185512 PMID:24217577 PMID:24398047 PMID:26836308
BS4 Not assessed Not assessed: no affected family members with genotype results are available to demonstrate lack of segregation.
PMID:24398047
BP1 Not met Not met: ESR1 disease-relevant evidence centers on recurrent activating missense mutations, not a primarily truncating mechanism.
oncokb PMID:24185510 PMID:24185512 PMID:24217577 PMID:24398047 PMID:26836308
BP2 Not assessed Not assessed: no pathogenic partner variant or phase result is documented, so trans or cis observation required for BP2 cannot be determined.
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: REVEL 0.914 is above the generic BP4 supporting threshold of <=0.29 for missense variants.
revel
BP5 Not assessed Not assessed: no case-level evidence shows D538G occurred with an established alternate molecular basis for the disease.
BP6 Not met Not met: ClinVar has no expert-panel Benign or Likely benign classification for exact D538G; its available record is single-submitter Oncogenic.
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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