Variant classification summary

NM_000125.4:c.1138G>C

ESR1 · NP_000116.2:p.(Glu380Gln) · NM_000125.4

GRCh37: chr6:152332832 G>C · GRCh38: chr6:152011697 G>C

Gene: ESR1 Transcript: NM_000125.4

Final call

VUS

PS3 supporting PM2 supporting PP3 moderate

Variant details

Gene

ESR1

Transcript

NM_000125.4

Protein

NP_000116.2:p.(Glu380Gln)

gnomAD AF

ClinVar

Likely oncogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: E380Q showed increased constitutive activity and greater estrogen sensitivity than wild-type ER.

2

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1.

3

PP3 moderate: REVEL 0.85 exceeds the moderate threshold of 0.773.

Final determination: Under the generic ACMG/AMP 2015 fallback, one moderate and two supporting pathogenic criteria satisfy no listed pathogenic or likely pathogenic combination, and no benign rule is met, so the result is VUS.

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: no validated pathogenic comparator producing ESR1 p.Glu380Gln through a different nucleotide change was available.	clinvar
PS2	Not assessed	Not assessed: no proband phenotype, family-history, or confirmed maternity-and-paternity testing data are available to establish a de novo occurrence.	PMID:8114756
PS3	Met	Met at supporting strength: E380Q required two- to threefold less estradiol and showed 8-fold higher estrogen-independent activity than wild-type ER.	PMID:8114756
PS4	Not met	Not met: no exact-variant case-control counts, odds ratio, or 95% confidence interval were reported, and the two PS4 candidate papers do not mention this variant.	PMID:22918138 PMID:34131312
PM1	Not assessed	Not assessed: E380 is in the hormone-binding domain, but no governing evidence establishes a qualifying critical domain without benign variation.	PMID:8114756 hotspots
PM2	Met	Met, supporting: the variant is absent from gnomAD v2.1 and v4.1, consistent with frequency 0 versus the PM2 <=0.0001 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no recessive-disease context, affected proband, pathogenic allele, or parent/offspring phase data establish ESR1 p.(Glu380Gln) in trans.	PMID:8114756
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: zero validated same-residue comparator variants with established pathogenic determinations were available for ESR1 residue 380.	pm5_candidates
PM6	Not assessed	Not assessed: no case-level de novo observation or parental testing information is available to support an assumed de novo variant.	PMID:8114756
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or cosegregation data are reported for this variant.	PMID:8114756
PP2	Not assessed	Not assessed: no evidence establishes both low benign missense variation and a common missense disease mechanism for ESR1.	gnomad_v2 gnomad_v4 oncokb
PP3	Met	Met at moderate strength: missense REVEL score 0.85 meets the >=0.773 PP3 moderate threshold.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family history was provided to evaluate specificity for a disease with a single genetic etiology.
PP5	Not met	Not met: ClinVar shows only a one-star single-submitter Likely oncogenic label, not an exact-variant expert-panel Pathogenic or Likely pathogenic classification.	clinvar PMID:22918138 PMID:34131312
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than reaching the >=5% allele-frequency threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 report no occurrence, so no allele frequency exceeds the generic 1% BS1 default.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no qualifying healthy-adult genotype observation is documented for a disorder with full penetrance expected at an early age.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: E380Q showed an 8-fold increase in activity without added estrogen rather than no damaging effect on ER function.	PMID:8114756
BS4	Not assessed	Not assessed: no affected relatives with documented variant-negative results are available to demonstrate lack of segregation.	PMID:8114756
BP1	Not assessed	Not assessed: no validated gene-level evidence shows that primarily truncating ESR1 variants are the known disease-causing mechanism.	oncokb
BP2	Not assessed	Not assessed: no documented pathogenic variant in trans or cis, and no patient or phase data are available for ESR1 p.(Glu380Gln).	PMID:8114756
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 0.85 exceeds the <=0.29 BP4 supporting threshold and remains computationally indeterminate.	revel
BP5	Not assessed	Not assessed: no case-level evidence showed this exact variant alongside an independently established alternate molecular basis for disease.
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign classification and instead reports one-star single-submitter Likely 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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