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ESR1c.1150C>GUncertain significance
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Variant interpretation report

ESR1 c.1150C>G, p.(Leu384Val)

NM_001122740.1:c.1150C>G NP_001116212.1:p.(Leu384Val) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About ESR1

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting

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.

PP3Supporting
PP3 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ESR1 (estrogen receptor alpha) is a transcription factor that is frequently mutated in hormone-resistant metastatic breast cancers.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 21 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

Met · 2

PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • v4.1 (exomes)
  • and gnomAD-Canada v1.0 (genomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL 0.863 (deleterious)
  • BayesDel 0.279 (damaging)
  • SpliceAI max delta 0.00 (no splice effect
  • consistent with missense mechanism).
Sources
revelbayesdelspliceai ↗

Not met · 21 · evaluated, threshold not reached

PS1 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. Details ▾Hide ▴
Evidence considered
  • ClinVar contains no variant entries at this residue
  • no pathogenic comparators exist.
Still missing
  • No ClinVar entries for any variant at Leu384.
Sources
clinvar ↗
PS2 No de novo occurrence data are available for this variant. No publications report de novo status, and no ClinVar submissions assert de novo inheritance. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no de novo reports in the literature.
Still missing
  • No family or trio sequencing data available for this variant.
Sources
clinvar ↗
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional studies found.
Still missing
  • No experimental functional data for p.Leu384Val or a systematically characterized range spanning residue 384.
Sources
oncokb ↗
PS4 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. Details ▾Hide ▴
Evidence considered
  • Variant absent from all population and disease databases
  • no case reports available.
Still missing
  • No case-control or cohort data exist for this variant.
Sources
gnomad_v2 ↗gnomad_v4 ↗clinvar ↗
PM1 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. Details ▾Hide ▴
Evidence considered
  • Residue 384 is in the ESR1 ligand-binding domain but is not a statistically significant hotspot (cancerhotspots.org negative)
  • no pathogenic ClinVar clustering at this residue.
Still missing
  • No domain-specific constraint data or ClinVar pathogenic enrichment at residue 384.
Sources
clinvar ↗
PM6 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. Details ▾Hide ▴
Evidence considered
  • No de novo evidence in ClinVar or the literature.
Still missing
  • No trio or parent-of-origin testing data available.
Sources
clinvar ↗
PP1 No cosegregation data are available. No family studies or linkage analyses have been performed for this variant. Details ▾Hide ▴
Evidence considered
  • No cosegregation or family-based studies identified.
Still missing
  • No family segregation data available for this variant.
PP2 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. Details ▾Hide ▴
Evidence considered
  • HCI prior not available for ESR1
  • no gene-level missense constraint data retrieved.
Still missing
  • No missense constraint metrics (Z-score
  • MTR) available for ESR1.
PP4 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. Details ▾Hide ▴
Evidence considered
  • No clinical phenotype or family history data provided.
Still missing
  • No clinical phenotype data available.
PP5 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. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no pathogenicity assertions from any source.
Sources
clinvar ↗
BA1 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
  • AF = 0.00%
  • far below BA1 threshold of >1%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
  • AF = 0.00%
  • below BS1 threshold of >0.3%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
  • no observation in healthy controls or in trans configurations.
Still missing
  • No data on trans configurations or healthy adult carriers.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no functional studies demonstrating benign effect.
Still missing
  • No functional studies exist for p.Leu384Val.
Sources
oncokb ↗
BS4 No segregation data are available for this variant. BS4 requires lack of cosegregation in affected family members, which cannot be assessed. Details ▾Hide ▴
Evidence considered
  • No family segregation data available.
Still missing
  • No segregation data available for this variant.
BP1 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. Details ▾Hide ▴
Evidence considered
  • ESR1 germline disease mechanism is not exclusively truncating
  • missense variants are an established disease mechanism in ESR1.
Sources
pvs1_gene_context
BP2 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. Details ▾Hide ▴
Evidence considered
  • Absent from all databases
  • no trans or cis configuration data available.
Still missing
  • No phase data available for this variant.
Sources
gnomad_v2 ↗gnomad_v4 ↗clinvar ↗
BP4 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. Details ▾Hide ▴
Evidence considered
  • REVEL 0.863 (deleterious)
  • BayesDel 0.279 (damaging). Computational evidence does not support a benign interpretation.
Sources
revelbayesdelspliceai ↗
BP5 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. Details ▾Hide ▴
Evidence considered
  • No alternate molecular diagnosis data available.
Still missing
  • No alternate molecular basis data for any case carrying this variant.
BP6 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. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no benign assertions from any source.
Sources
clinvar ↗
PS5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar entirely; no pathogenicity assertions exist from any submitter. Details ▾Hide ▴
Evidence considered
  • ClinVar contains no entries and no pathogenicity assertions for this variant.
Sources
clinvar ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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. Details ▾Hide ▴
Evidence considered
  • Missense substitution c.1150C>G (p.Leu384Val) does not qualify for PVS1 under generic null-variant criteria.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/ANo trans configuration data available to assess recessive inheritance. PM3 is trivially not applicable. Details ▾Hide ▴
Evidence considered
  • No trans data available for recessive assessment.
PM4 N/AVariant is a substitution, not a protein-length-altering change (in-frame deletion/insertion or stop-loss). PM4 is trivially not applicable. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not a protein-length-altering variant.
PM5 N/ANo 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. Details ▾Hide ▴
Evidence considered
  • No pathogenic missense variants at Leu384 identified in ClinVar or the literature.
Sources
pm5_candidatesclinvar ↗
BP3 N/AVariant is a substitution, not an in-frame indel in a non-repeat region. BP3 is trivially not applicable. Details ▾Hide ▴
Evidence considered
  • Substitution variant
  • not an in-frame indel.
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
  • Missense variant (p.Leu384Val)
  • BP7 is only applicable to synonymous variants.

Identifiers

Gene
ESR1
Transcript
NM_001122740.1
Coding (HGVS c.)
NM_001122740.1:c.1150C>G
Protein (HGVS p.)
NP_001116212.1:p.(Leu384Val)
GRCh38
chr6:152011709 C>G
GRCh37
chr6:152332844 C>G

Gene diagram

Every interpreted variant in ESR1, mapped onto the exon structure of NM_001122740.1. Select a row to find it on the plot.

ESR1NM_001122740.1
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -24 bp
0.000
SpliceAI acceptor gainat -75 bp
0.000
SpliceAI donor lossat +85 bp
0.000
SpliceAI donor gainat -25 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.863
BayesDel
0.279

How the predictions were used

PP3 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL 0.863 (deleterious)
  • BayesDel 0.279 (damaging)
  • SpliceAI max delta 0.00 (no splice effect
  • consistent with missense mechanism).
Sources
revelbayesdelspliceai ↗
BP4 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. Details ▾Hide ▴
Evidence considered
  • REVEL 0.863 (deleterious)
  • BayesDel 0.279 (damaging). Computational evidence does not support a benign interpretation.
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 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. Details ▾Hide ▴
Evidence considered
  • Missense variant (p.Leu384Val)
  • BP7 is only applicable to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.863. BayesDel score = 0.278555.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.863. BayesDel score = 0.278555.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ESR1 (estrogen receptor alpha) is a transcription factor that is frequently mutated in hormone-resistant metastatic breast cancers.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.