About ESR1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ESR1 c.173C>T, p.(Ala58Val)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_001122740.1:c.173C>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes + genomes), and gnomAD-Canada v1.0. Per generic ACMG/AMP guidelines, absence from population databases at an allele frequency below 0.1% qualifies as PM2 at supporting strength.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score 0.092 is well below the 0.5 threshold for damaging prediction. BayesDel score -0.418 is below the 0.0 threshold for deleterious prediction. SpliceAI max delta score is 0.00, predicting no splice alteration. Per generic ACMG/AMP guidelines, concordant benign predictions from multiple in silico tools support BP4 at supporting benign strength.
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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
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
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 15 not met · 3 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001122740.1:c.173C>T (p.Ala58Val) in ESR1 is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying PM2 at supporting strength.
Multiple in silico tools predict a benign effect: REVEL score 0.092, BayesDel score -0.418, and SpliceAI max delta 0.00. These concordant benign predictions satisfy BP4 at supporting benign strength.
No functional data, segregation data, de novo reports, case-control studies, or ClinVar classifications exist for this variant. All other assessed criteria are either not met or not applicable.
The evidence is conflicting: one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) result in indeterminate classification. Under generic ACMG/AMP 2015 combination rules, this variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingNM_001122740.1:c.173C>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes + genomes), and gnomAD-Canada v1.0. Per generic ACMG/AMP guidelines, absence from population databases at an allele frequency below 0.1% qualifies as PM2 at supporting strength. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada v1.0
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score 0.092 is well below the 0.5 threshold for damaging prediction. BayesDel score -0.418 is below the 0.0 threshold for deleterious prediction. SpliceAI max delta score is 0.00, predicting no splice alteration. Per generic ACMG/AMP guidelines, concordant benign predictions from multiple in silico tools support BP4 at supporting benign strength. Details ▾Hide ▴
Evidence considered
- REVEL score 0.092 (benign
- below 0.5 threshold)
- BayesDel score -0.418 (benign
- below 0.0 threshold)
- SpliceAI max delta 0.0 (no splicing impact predicted)
Sources
Not met · 15 · evaluated, threshold not reached
PS2 No de novo data available for this variant. No publications or ClinVar submissions report de novo occurrence of NM_001122740.1:c.173C>T. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no de novo reporting in any source
Still missing
- No parental testing data available
Sources
PS3 No functional data exists for NM_001122740.1:c.173C>T (p.A58V). OncoKB reports unknown oncogenic effect. No literature describes experimental characterization of this variant or a systematically characterized range that includes residue 58. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional studies identified
Still missing
- No functional studies of p.A58V or saturation mutagenesis spanning residue 58
Sources
PS4 No case-control or statistical evidence of enrichment in affected individuals. The variant is absent from all population databases, precluding prevalence comparison. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD and ClinVar
- no case-control data available
Still missing
- No case-control studies or cohort data
Sources
PM1 The p.A58V substitution lies in the N-terminal AF-1 domain of ESR1, but this position is not a statistically significant mutational hotspot (cancerhotspots.org negative). Without an established germline disease-associated mutational hotspot or a defined functional domain where pathogenic missense variants are enriched in ESR1 germline disease, PM1 is not met. Details ▾Hide ▴
Evidence considered
- Not a significant hotspot at cancerhotspots.org
- no germline disease mutational spectrum defined for ESR1
Still missing
- ESR1 germline disease mutational spectrum not well-characterized
PM6 No de novo data available. No publications or ClinVar submissions report de novo occurrence of this variant. Without confirmed maternity/paternity, PM6 cannot be applied. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no de novo reporting
Still missing
- No parental testing data available
Sources
PP1 No segregation data available. No family studies or cosegregation analysis has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data in any source
Still missing
- No family studies or cosegregation data
PP3 Multiple in silico tools predict a benign effect: REVEL score 0.092 (below 0.5 threshold), BayesDel score -0.418 (below 0.0 threshold), SpliceAI max delta 0.0 (no splice impact). No computational tool supports a damaging prediction. Details ▾Hide ▴
Evidence considered
- REVEL score 0.092 (benign)
- BayesDel score -0.418 (benign)
- SpliceAI max delta 0.0 (no splicing impact)
Sources
PP5 No reputable source (clinical diagnostic laboratory, expert panel) has classified this variant as pathogenic. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no pathogenic classification from any reputable source
Sources
BA1 The variant is absent from all population databases (gnomAD v2.1, v4.1, Canada). The allele frequency is 0%, far below the 1% threshold required for BA1. Details ▾Hide ▴
Evidence considered
- Allele frequency 0% across all gnomAD datasets
- below 1% BA1 threshold
Sources
BS1 The variant is absent from all population databases. The allele frequency is 0%, below the 0.3% threshold required for BS1. Absence does not satisfy BS1; a population frequency greater than expected for the disorder is required. Details ▾Hide ▴
Evidence considered
- Allele frequency 0% across all gnomAD datasets
- below 0.3% BS1 threshold
Sources
BS2 The variant has not been observed in any population database, so there is no evidence of observation in healthy adults. BS2 requires confirmed observation in a healthy adult individual for a fully penetrant disorder. Details ▾Hide ▴
Evidence considered
- Variant not observed in any population database
- no evidence of presence in healthy controls
Sources
BS3 No functional studies have been performed on this variant demonstrating no deleterious effect. OncoKB reports unknown oncogenic effect with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no functional studies demonstrating benign effect
Still missing
- No functional studies of p.A58V
Sources
BS4 No segregation data available to demonstrate lack of cosegregation with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No family segregation data available
Still missing
- No family studies
BP2 No observation data available regarding trans configuration with a pathogenic variant. The variant is absent from population databases, and no clinical reports describe compound heterozygosity. Details ▾Hide ▴
Evidence considered
- No trans observation data available
Still missing
- No data on co-occurrence with pathogenic variants
BP6 No reputable source classifies this variant as benign. The variant is absent from ClinVar entirely; no diagnostic laboratory or expert panel has issued a benign classification. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no benign classification from any reputable source
Sources
Not assessed · 3 · no assessment recorded
PP2 PP2 requires the gene to have a low rate of benign missense variation and missense variants to be a common disease mechanism. No HCI prior or missense constraint data (e.g., gnomAD Z-score) is available for ESR1. The gene is not a well-established germline disease gene, so the missense constraint profile cannot be reliably evaluated. Details ▾Hide ▴
Evidence considered
- No HCI prior available
- no missense constraint metric for ESR1
Still missing
- Missense constraint score (Z-score) not available
- germline disease mechanism uncertain
PP4 No proband phenotype or clinical indication is provided in the case materials. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. Without phenotype data, this criterion cannot be evaluated. Details ▾Hide ▴
Evidence considered
- No proband phenotype or clinical history available
Still missing
- Proband phenotype and clinical indication not provided
BP5 No information is available regarding an alternative molecular basis for disease in the proband. BP5 requires a confirmed alternate molecular cause for the observed phenotype. Details ▾Hide ▴
Evidence considered
- No alternate molecular cause data available
Still missing
- Proband clinical workup and alternative genetic findings not provided
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.173C>T, p.Ala58Val). PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice consensus). The variant falls into the 'other' bucket per ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- NM_001122740.1:c.173C>T is a missense substitution producing p.Ala58Val
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ANo pathogenic variant at codon 58 (p.Ala58) with a different nucleotide change has been reported in ClinVar. PS1 requires an established pathogenic variant at the same amino acid position. Details ▾Hide ▴
Evidence considered
- No ClinVar entries at codon 58 of ESR1 with a pathogenic classification
Sources
PM5 N/ANo pathogenic missense variant at the same amino acid position (p.Ala58) has been identified. The PM5 candidate search returned zero same-residue comparator variants in ClinVar. Details ▾Hide ▴
Evidence considered
- Zero same-residue comparator variants at codon 58 of ESR1
Sources
pm5_candidatesclinvar ↗
BP1 N/ABP1 applies to missense variants in genes where only truncating variants cause disease. ESR1 is not established as a gene where the sole disease mechanism is loss-of-function via truncation. In somatic cancer, activating missense mutations in ESR1 are well-characterized. Details ▾Hide ▴
Evidence considered
- ESR1 is not a gene where only truncating variants cause disease
BP7 N/ABP7 is reserved for synonymous (silent) variants with no predicted splice impact. NM_001122740.1:c.173C>T is a missense variant producing p.Ala58Val, not a synonymous variant. Details ▾Hide ▴
Evidence considered
- c.173C>T is a missense substitution (p.Ala58Val)
- not synonymous
PS5 N/ANo reputable source has classified this variant as pathogenic. The variant is absent from ClinVar entirely, and no clinical laboratory has reported it as pathogenic. PS5 requires a prior pathogenic assertion by a reputable source. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no pathogenic classification from any source
Sources
Identifiers
- Gene
- ESR1
- Transcript
- NM_001122740.1
- Coding (HGVS c.)
- NM_001122740.1:c.173C>T
- Protein (HGVS p.)
- NP_001116212.1:p.(Ala58Val)
- GRCh38
- chr6:151808085 C>T
- GRCh37
- chr6:152129220 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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in ESR1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
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
Other predictors
- REVEL
- 0.092
- BayesDel
- -0.418
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score 0.092 is well below the 0.5 threshold for damaging prediction. BayesDel score -0.418 is below the 0.0 threshold for deleterious prediction. SpliceAI max delta score is 0.00, predicting no splice alteration. Per generic ACMG/AMP guidelines, concordant benign predictions from multiple in silico tools support BP4 at supporting benign strength. Details ▾Hide ▴
Evidence considered
- REVEL score 0.092 (benign
- below 0.5 threshold)
- BayesDel score -0.418 (benign
- below 0.0 threshold)
- SpliceAI max delta 0.0 (no splicing impact predicted)
Sources
PP3 Multiple in silico tools predict a benign effect: REVEL score 0.092 (below 0.5 threshold), BayesDel score -0.418 (below 0.0 threshold), SpliceAI max delta 0.0 (no splice impact). No computational tool supports a damaging prediction. Details ▾Hide ▴
Evidence considered
- REVEL score 0.092 (benign)
- BayesDel score -0.418 (benign)
- SpliceAI max delta 0.0 (no splicing impact)
Sources
BP7 N/ABP7 is reserved for synonymous (silent) variants with no predicted splice impact. NM_001122740.1:c.173C>T is a missense variant producing p.Ala58Val, not a synonymous variant. Details ▾Hide ▴
Evidence considered
- c.173C>T is a missense substitution (p.Ala58Val)
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.092. BayesDel score = -0.418096.
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_001122740.1%3Ac.173C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/6-152129220-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr6-151808085-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/6-151808085-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001122740.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/ESR1/A58V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ESR1+c.173C%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
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 = 0.092. BayesDel score = -0.418096.
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.