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ESR1c.1519C>TUncertain significance
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Variant interpretation report

ESR1 c.1519C>T, p.(Leu507Phe)

NM_001122740.1:c.1519C>T NP_001116212.1:p.(Leu507Phe) 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: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PP3Supporting
PP3 · supporting

REVEL score of 0.916 strongly predicts a deleterious effect on protein function (threshold >0.75 for pathogenic prediction). This integrative in silico score provides supporting computational evidence for a damaging effect, though BayesDel is intermediate (0.456) and SpliceAI shows no splicing impact (max delta 0.01).

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: PP3 supporting; combination = 1 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.

No screenshot for this evidence
Population frequency
Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. 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: 1 met · 17 not met · 6 not assessed · 5 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.1519C>T (p.Leu507Phe) is a missense variant in exon 8 of ESR1, encoding the estrogen receptor alpha.

This variant is absent from ClinVar and has not been reported in the literature as a germline variant.

In silico analysis with REVEL predicts a deleterious effect (score 0.916), providing supporting evidence for pathogenicity (PP3).

Population frequency data from gnomAD v2.1 and v4.1 is unavailable due to technical limitations; gnomAD-Canada reports the variant as absent.

No functional studies, family segregation data, or clinical case reports were identified for this variant in the literature or curated databases.

Overall, the available evidence is insufficient to classify this variant under ACMG/AMP 2015 guidelines; the sole met criterion (PP3 supporting) does not reach the threshold for likely pathogenic or likely benign classification. Variant remains a variant of uncertain significance (VUS).

Met · 1

PP3 SupportingREVEL score of 0.916 strongly predicts a deleterious effect on protein function (threshold >0.75 for pathogenic prediction). This integrative in silico score provides supporting computational evidence for a damaging effect, though BayesDel is intermediate (0.456) and SpliceAI shows no splicing impact (max delta 0.01). Details ▾Hide ▴
Evidence considered
  • REVEL score 0.916 (pathogenic)
  • BayesDel score 0.456 (intermediate)
  • SpliceAI max delta 0.01 (no splicing impact).
Sources
revelbayesdelspliceai ↗

Not met · 17 · evaluated, threshold not reached

PS1 No alternative nucleotide change at c.1519 predicted to produce the same amino acid change (p.Leu507Phe) has been reported as pathogenic in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no same-amino-acid pathogenic comparator identified.
Sources
clinvar ↗
PS3 No functional studies of NM_001122740.1:c.1519C>T (p.Leu507Phe) were identified in the literature or curated databases. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional studies identified. No PMIDs with functional data for this variant were found.
Still missing
  • No in vitro or in vivo functional characterization of p.Leu507Phe is available.
Sources
oncokb ↗
PS4 This variant is absent from ClinVar and has not been identified in any clinical cohort or case-control study; no prevalence data exists to support PS4. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no case-control or cohort data available.
Still missing
  • No case-control studies or clinical cohort data identified for this variant.
Sources
clinvar ↗
PM1 p.Leu507Phe lies within the ligand-binding domain (LBD) of ESR1, a well-characterized functional domain. However, this residue is not a statistically significant hotspot at cancerhotspots.org, and the missense variant does not demonstrably remove or truncate the domain. Without either hotspot evidence or functional data confirming domain disruption, PM1 is not met for a missense variant. Details ▾Hide ▴
Evidence considered
  • Residue L507 is within the ESR1 ligand-binding domain (residues ~302-552)
  • but cancerhotspots.org does not identify L507 as a statistically significant hotspot.
Still missing
  • No functional data confirming whether p.Leu507Phe disrupts LBD function.
PM5 No other pathogenic missense variant at codon 507 (Leu507) was identified in ClinVar. The PM5 candidate search returned zero same-residue comparator variants. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search found zero same-residue (Leu507) pathogenic missense variants in ClinVar.
Sources
pm5_candidatesclinvar ↗
PP1 No co-segregation data is available for this variant. Details ▾Hide ▴
Evidence considered
  • No family studies or co-segregation data identified.
Still missing
  • No family segregation studies available.
PP5 This variant is absent from ClinVar. No reputable clinical source has reported it as pathogenic. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no pathogenic classification from any submitter.
Sources
clinvar ↗
BA1 This variant is absent from available population databases; allele frequency does not exceed the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • Variant absent from gnomAD-Canada
  • no population allele frequency data exceeds 1%.
Still missing
  • gnomAD v2.1/v4.1 data unavailable (timeout).
Sources
gnomad_canada ↗
BS2 No data is available on observation of this variant in healthy adult individuals for a fully penetrant disorder. Details ▾Hide ▴
Evidence considered
  • No data on healthy adult carriers or incomplete penetrance.
Still missing
  • No clinical observation data in healthy adults.
BS3 No well-established in vitro or in vivo functional studies were identified in the literature or curated databases demonstrating no damaging effect of this variant. Details ▾Hide ▴
Evidence considered
  • OncoKB reports Unknown Oncogenic Effect
  • no functional studies identified.
Still missing
  • No functional characterization studies available.
Sources
oncokb ↗
BS4 No family segregation data is available to support lack of segregation in affected family members. Details ▾Hide ▴
Evidence considered
  • No family studies or segregation data identified.
Still missing
  • No segregation data available.
BP1 ESR1-related disease is not primarily caused by truncating variants. Missense variants in the ligand-binding domain are a well-documented mechanism in hormone-resistant breast cancer. Details ▾Hide ▴
Evidence considered
  • ESR1 missense variants in the LBD are established drivers in breast cancer
  • truncating variants are not the sole disease mechanism.
Sources
oncokb ↗
BP2 No phase data (in trans or in cis with other pathogenic variants) is available for this variant. Details ▾Hide ▴
Evidence considered
  • No cis/trans phase data available.
Still missing
  • No phase data with other pathogenic variants.
BP4 REVEL score of 0.916 strongly predicts a deleterious effect, contradicting the absence of functional impact. Although SpliceAI shows no splicing impact (max delta 0.01), the strong REVEL prediction precludes application of BP4. Details ▾Hide ▴
Evidence considered
  • REVEL 0.916 predicts damaging
  • SpliceAI 0.01 predicts no splicing impact. The damaging prediction outweighs neutral splicing evidence.
Sources
revelspliceai ↗bayesdel
BP5 No data is available on an alternate molecular basis for disease in cases with this variant. Details ▾Hide ▴
Still missing
  • No alternate molecular diagnosis data available.
BP6 This variant is absent from ClinVar. No reputable clinical source has reported it as benign. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no benign classification from any submitter.
Sources
clinvar ↗
PS5 No previously established pathogenic variant with the same amino acid change (p.Leu507Phe) was identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no same-amino-acid pathogenic variant identified at any nucleotide position.
Sources
clinvar ↗

Not assessed · 6 · no assessment recorded

PS2 No de novo data or family studies are available for this variant in the case materials. Details ▾Hide ▴
Still missing
  • No parental testing or de novo confirmation data available.
PM2 gnomAD v2.1 and v4.1 population frequency data is unavailable due to scraping timeout. gnomAD-Canada v1.0 reports the variant as absent, but this dataset alone is insufficient to establish population absence at the confidence required for PM2. Details ▾Hide ▴
Evidence considered
  • gnomAD-Canada v1.0 reports absent (AC=0)
  • gnomAD v2.1 and v4.1 data not retrieved (timeout).
Still missing
  • gnomAD v2.1 and v4.1 population frequency data unavailable
  • manual lookup recommended.
Sources
gnomad_canada ↗
PM6 No de novo or family segregation data is available for this variant in the case materials or literature. Details ▾Hide ▴
Still missing
  • No parental testing or de novo data available.
PP2 gnomAD constraint data is unavailable (scraping timeout), preventing assessment of the rate of benign missense variation in ESR1. Without constraint metrics, PP2 cannot be securely applied. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1/v4.1 data missing
  • cannot assess rate of benign missense variation.
Still missing
  • gnomAD constraint metrics (Z-score
  • pLI
  • missense o/e) unavailable
  • manual lookup recommended.
PP4 No patient phenotype or family history data is available to assess whether the clinical presentation is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
  • Patient phenotype and family history data not provided.
BS1 gnomAD v2.1 and v4.1 population frequency data is unavailable due to scraping timeout. Without the primary population databases, the allele frequency cannot be compared to the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1/v4.1 data not retrieved (timeout).
Still missing
  • gnomAD v2.1 and v4.1 allele frequency data unavailable
  • manual lookup recommended.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001122740.1:c.1519C>T is a missense substitution (p.Leu507Phe), not a null variant (nonsense, frameshift, or canonical ±1,2 splice). Generic PVS1 framework (PMC6185798) requires a null-type variant; this variant is in the 'other' bucket. Details ▾Hide ▴
Evidence considered
  • Missense variant p.Leu507Phe does not fall into PVS1 null-variant buckets (nonsense
  • frameshift
  • or canonical ±1
  • 2 splice consensus variants).
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 requires identification of the variant in trans with a pathogenic variant for recessive disorders; no trans-phase data is available for this autosomal gene. Details ▾Hide ▴
Evidence considered
  • No phase data available
  • variant absent from population databases.
PM4 N/APM4 applies to non-repeat protein length changes (in-frame deletions/insertions, stop-loss); this is a missense substitution. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not a protein length-altering variant.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this is a single-nucleotide substitution. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not an in-frame indel.
BP7 N/ANM_001122740.1:c.1519C>T is a missense variant (p.Leu507Phe), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not synonymous.

Identifiers

Gene
ESR1
Transcript
NM_001122740.1
Coding (HGVS c.)
NM_001122740.1:c.1519C>T
Protein (HGVS p.)
NP_001116212.1:p.(Leu507Phe)
GRCh38
chr6:152094534 C>T
GRCh37
chr6:152415669 C>T

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-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -182 bp
0.000
SpliceAI acceptor gainat -127 bp
0.010
SpliceAI donor lossat +25 bp
0.000
SpliceAI donor gainat +34 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.916
BayesDel
0.456

How the predictions were used

PP3 SupportingREVEL score of 0.916 strongly predicts a deleterious effect on protein function (threshold >0.75 for pathogenic prediction). This integrative in silico score provides supporting computational evidence for a damaging effect, though BayesDel is intermediate (0.456) and SpliceAI shows no splicing impact (max delta 0.01). Details ▾Hide ▴
Evidence considered
  • REVEL score 0.916 (pathogenic)
  • BayesDel score 0.456 (intermediate)
  • SpliceAI max delta 0.01 (no splicing impact).
Sources
revelbayesdelspliceai ↗
BP4 REVEL score of 0.916 strongly predicts a deleterious effect, contradicting the absence of functional impact. Although SpliceAI shows no splicing impact (max delta 0.01), the strong REVEL prediction precludes application of BP4. Details ▾Hide ▴
Evidence considered
  • REVEL 0.916 predicts damaging
  • SpliceAI 0.01 predicts no splicing impact. The damaging prediction outweighs neutral splicing evidence.
Sources
revelspliceai ↗bayesdel
BP7 N/ANM_001122740.1:c.1519C>T is a missense variant (p.Leu507Phe), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.916. BayesDel score = 0.456408.

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.

SpliceAI Lookup Recorded maximum delta 0.010 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-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 = 0.01). REVEL score = 0.916. BayesDel score = 0.456408.

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.