NM_001122740.1:c.1150C>G

ESR1 · NP_001116212.1:p.(Leu384Val) · NM_001122740.1

GRCh37: chr6:152332844 C>G · GRCh38: chr6:152011709 C>G

Gene: ESR1 Transcript: NM_001122740.1

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

ESR1

Transcript

NM_001122740.1

Protein

NP_001116212.1:p.(Leu384Val)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001122740.1:c.1150C>G (p.Leu384Val) is a missense variant in ESR1 exon 6. It is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 across all populations (PM2_Supporting).

Multiple in silico predictors support a deleterious effect: REVEL score 0.863 and BayesDel score 0.279 both exceed their respective pathogenicity thresholds (PP3_Supporting).

The variant is absent from ClinVar, COSMIC, and all population databases. No functional studies, case reports, cosegregation data, or de novo observations exist for this variant.

PVS1 is not applicable as this is a missense variant that does not fall into the null-variant buckets per ClinGen SVI PVS1 recommendations (PMC6185798).

This variant does not lie in a statistically significant mutational hotspot (cancerhotspots.org negative), and no pathogenic ClinVar variants cluster at residue Leu384. PM1 is not met.

No publications were identified that mention NM_001122740.1:c.1150C>G. A targeted review of five ESR1 germline disease-context publications (PMID:15361840, PMID:25139996, PMID:41129222, PMID:22086303, PMID:26557847) confirmed none contain variant-specific evidence.

Overall classification: Variant of Uncertain Significance (VUS). Two supporting-level pathogenic criteria (PM2_Supporting, PP3_Supporting) are met, which is insufficient to reach Likely Pathogenic under the generic ACMG/AMP 2015 classification rules (PMID:25741868). No benign criteria are met.

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	NM_001122740.1:c.1150C>G is a missense variant (p.Leu384Val). It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). PVS1 is not applicable to missense variants under the generic ACMG/AMP framework.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No alternative nucleotide change at the same amino acid position (Leu384) with a pathogenic classification has been identified. The variant is absent from ClinVar, and no same-residue comparators exist in the literature or public databases.	clinvar
PS2	Not met	No de novo occurrence data are available for this variant. No publications report de novo status, and no ClinVar submissions assert de novo inheritance.	clinvar
PS3	Not met	No functional studies have been identified for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No publications describe experimental characterization of p.Leu384Val or a systematically characterized range that includes this residue. Domain-level inference from the ESR1 ligand-binding domain does not satisfy PS3's requirement for variant-level or systematically-characterized-range functional data.	oncokb
PS4	Not met	No case-control or cohort studies have reported this variant. The variant is absent from ClinVar, gnomAD, and COSMIC. No publications identify this variant in affected individuals.	gnomad_v2 gnomad_v4 clinvar
PS5	Not met	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar entirely; no pathogenicity assertions exist from any submitter.	clinvar
PM1	Not met	This variant (p.Leu384Val) lies within the ESR1 ligand-binding domain (aa ~302-552), a well-characterized functional domain. However, the cancerhotspots.org analysis did not identify this residue as a statistically significant mutational hotspot, and no ClinVar pathogenic variants cluster at this specific position. In the absence of a statistically significant hotspot or domain-level constraint data showing absence of benign variation, PM1 cannot be applied under generic ACMG/AMP rules.	clinvar
PM2	Met	NM_001122740.1:c.1150C>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 across all populations. This satisfies the generic ACMG/AMP PM2 threshold of <0.1% allele frequency in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variants with a pathogenic classification were identified. The pm5_candidates automation found zero same-residue candidates, and the variant is entirely absent from ClinVar. Classic PM5 semantics cannot be applied.	pm5_candidates clinvar
PM6	Not met	No de novo occurrence has been reported for this variant. No publications describe confirmed de novo status, and no ClinVar submissions assert de novo inheritance.	clinvar
PP1	Not met	No cosegregation data are available. No family studies or linkage analyses have been performed for this variant.
PP2	Not met	PP2 requires demonstration that the gene has a low rate of benign missense variation and that missense variants are a common disease mechanism. No HCI prior score is available for ESR1, and no gene-level missense constraint metrics (e.g., missense Z-score, Missense Tolerance Ratio) were retrieved. PP2 cannot be applied without this evidence.
PP3	Met	Multiple in silico predictors support a deleterious effect. REVEL score is 0.863 (above the 0.75 threshold for pathogenicity). BayesDel score is 0.279 (above the 0.27 damaging threshold). SpliceAI max delta is 0.00, which is expected for a missense variant without predicted splice effect. The concordance of protein-level predictors supports PP3 at supporting level.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data are available. PP4 requires a phenotype highly specific for a disease with a single genetic etiology, which cannot be assessed without clinical information.
PP5	Not met	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar, and no diagnostic laboratory or expert panel has issued a pathogenicity assertion.	clinvar
BA1	Not met	The variant is absent from all gnomAD populations (v2.1, v4.1, Canada v1.0). The allele frequency is 0.00%, which does not meet the BA1 threshold of >1% in any population.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all gnomAD populations. The allele frequency is 0.00%, which does not meet the BS1 threshold of >0.3% in any population.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data are available showing observation of this variant in a healthy adult for a recessive disorder, or in trans with a pathogenic variant for a dominant disorder. The variant is absent from all population databases, precluding observation in healthy controls.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrate a benign effect for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. No publications describe experimental characterization of p.Leu384Val showing normal protein function.	oncokb
BS4	Not met	No segregation data are available for this variant. BS4 requires lack of cosegregation in affected family members, which cannot be assessed.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. The PVS1 gene context review identified germline disease associations for ESR1 but did not establish that truncating variants are the primary disease mechanism. Missense variants in ESR1 are well-documented in disease (e.g., somatic activating mutations in breast cancer). BP1 is not supported.	pvs1_gene_context
BP2	Not met	No data are available showing observation of this variant in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant. The variant is absent from population and clinical databases.	gnomad_v2 gnomad_v4 clinvar
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact. REVEL score is 0.863 (deleterious) and BayesDel is 0.279 (damaging), both indicating a deleterious effect. SpliceAI max delta is 0.00, but this is expected for a missense variant acting through protein-level mechanisms. The computational evidence does not support a benign interpretation.	revel bayesdel spliceai
BP5	Not met	No evidence is available showing this variant in a case with an alternate molecular basis for disease. BP5 cannot be applied without clinical or molecular data demonstrating an alternative etiology.
BP6	Not met	No reputable source has reported this variant as benign. The variant is absent from ClinVar, and no benign assertions exist from any diagnostic laboratory or expert panel.	clinvar
BP7	N/A	BP7 applies exclusively to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_001122740.1:c.1150C>G is a missense variant (p.Leu384Val), not a synonymous variant. BP7 is not applicable.
BP3	N/A	Variant is a substitution, not an in-frame indel in a non-repeat region. BP3 is trivially not applicable.
PM3	N/A	No trans configuration data available to assess recessive inheritance. PM3 is trivially not applicable.
PM4	N/A	Variant is a substitution, not a protein-length-altering change (in-frame deletion/insertion or stop-loss). PM4 is trivially not applicable.

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