About ESR1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ESR1 c.1661G>A, p.(Ser554Asn)
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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is extremely rare in population databases: gnomAD v2.1 allele frequency 7.07×10⁻⁶ (2/282,762 alleles), gnomAD v4.1 allele frequency 1.86×10⁻⁶ (3/1,614,058 alleles), grpmax FAF 7.39×10⁻⁶. All frequencies are well below the 0.1% PM2 threshold. Absent from gnomAD-Canada.
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; 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
3 / 1,614,058 alleles
gnomAD v4.1: 3 / 1,614,058 alleles. Recorded AF 1.85867e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.07309e-06; MAF= 0.00071%, 2/282762 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.01153e-05; MAF= 0.00501%, 1/19954 alleles, homozygotes = 0).
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.
No listed criterion applied
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
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
27 criteria with recorded statuses: 1 met · 18 not met · 4 not assessed · 4 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.1661G>A (p.Ser554Asn) is a missense variant in exon 9 of ESR1 encoding estrogen receptor alpha.
The variant is extremely rare in population databases: gnomAD v2.1 allele frequency 7.07×10⁻⁶ (2/282,762 alleles) and gnomAD v4.1 allele frequency 1.86×10⁻⁶ (3/1,614,058 alleles), both well below the 0.1% threshold for PM2 at supporting strength.
The variant is absent from ClinVar; no clinical laboratory or expert panel classification exists.
No functional studies, de novo observations, segregation data, case-control comparisons, or literature citations mentioning this specific variant were identified.
In silico predictors are mixed: BayesDel (−0.538) predicts benign, SpliceAI (max delta 0.0) predicts no splicing alteration, and REVEL (0.213) is in the indeterminate range.
Residue 554 lies C-terminal to the ligand-binding domain (LBD, aa ~302–552) and is not within a known critical functional domain or statistically significant mutational hotspot.
PVS1 does not apply (missense variant); PM5 does not apply (no same-residue comparator variants identified).
The only applicable criterion is PM2 at supporting strength. Per ACMG/AMP 2015 classification rules (PMID:25741868), a single supporting pathogenic criterion without any other evidence is insufficient for classification as likely pathogenic or pathogenic.
This variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 1
PM2 SupportingThis variant is extremely rare in population databases: gnomAD v2.1 allele frequency 7.07×10⁻⁶ (2/282,762 alleles), gnomAD v4.1 allele frequency 1.86×10⁻⁶ (3/1,614,058 alleles), grpmax FAF 7.39×10⁻⁶. All frequencies are well below the 0.1% PM2 threshold. Absent from gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=7.07e-06 (2/282
- 762
- 0 hom)
- best subpop EAS AF=5.01e-05 (1/19
- 954). gnomAD v4.1: AF=1.86e-06 (3/1
- 614
- 058
- grpmax FAF=7.39e-06. gnomAD-Canada: absent.
Sources
Not met · 18 · evaluated, threshold not reached
PS1 No known pathogenic variant with a different amino acid change at the same position (Ser554) has been reported in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- ClinVar contains no entries for NM_001122740.1:c.1661G>A or any other variant at codon 554. PM5 candidate search returned no same-residue comparator variants.
Sources
clinvar ↗pm5_candidates
PS2 No de novo observation with confirmed maternity and paternity has been reported for this variant in the literature or ClinVar. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no de novo submissions or reports identified.
Sources
PS3 No experimental functional studies testing this exact variant or a systematically characterized range that includes residue 554 were identified. OncoKB reports 'Unknown Oncogenic Effect.' In silico predictors (REVEL 0.213, BayesDel −0.538) do not support a damaging functional effect. Details ▾Hide ▴
Evidence considered
- OncoKB: no variant-specific functional evidence
- classification 'Unknown Oncogenic Effect'. REVEL 0.213 (indeterminate). BayesDel −0.538 (benign-leaning). No PMIDs with functional data.
Still missing
- No experimental functional data exist for this variant.
Sources
PM1 Residue 554 lies C-terminal to the ESR1 ligand-binding domain (LBD, residues ~302–552) and AF-2 activation helix (helix 12, ~535–552); it is not within a known critical functional domain. Neither the residue nor the exact variant is a statistically significant mutational hotspot (cancerhotspots.org). Details ▾Hide ▴
Evidence considered
- Hotspot analysis: residue 554 is not statistically significant
- exact variant not listed. OncoKB: 'Unknown Oncogenic Effect'
- no curated functional domain hit at this position. Residue 554 is in the flexible C-terminal tail
- 2 residues beyond the LBD boundary.
Sources
PM6 No de novo observation has been reported for this variant in the literature or ClinVar; PM6 requires confirmed de novo status with maternity/paternity testing. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no de novo reports identified in any available source.
Sources
PP1 No co-segregation data are available for this variant in affected families. Details ▾Hide ▴
Evidence considered
- No family studies or segregation analysis identified in ClinVar or literature.
Still missing
- No segregation data available.
PP2 ESR1 is not recognized as a gene where missense variants are a well-established predominant mechanism of germline disease. While somatic missense mutations in ESR1 are well-described in hormone-resistant breast cancer, the gene lacks a well-characterized germline disease spectrum meeting PP2 criteria. Details ▾Hide ▴
Evidence considered
- OncoKB gene summary: ESR1 mutations occur somatically in hormone-resistant metastatic breast cancer. No established germline syndrome where missense is the predominant pathogenic mechanism.
Sources
oncokb ↗pvs1_gene_context
PP3 In silico tools do not support a deleterious effect: REVEL score 0.213 is in the indeterminate range (threshold for pathogenicity >0.5), BayesDel score −0.538 is negative (predicts benign), and SpliceAI max delta score is 0.0 (no predicted splicing impact). No HCI prior score is available for ESR1. Details ▾Hide ▴
Evidence considered
- REVEL: 0.213 (indeterminate). BayesDel: −0.538 (benign). SpliceAI: max delta 0.0 (no splice effect). HCI prior: gene not supported.
Sources
PP5 The variant is absent from ClinVar; no reputable clinical laboratory or expert panel has classified this variant as pathogenic. PP5 requires a classification from a source with supporting-level credibility (ClinVar 1-star submitter or higher). Details ▾Hide ▴
Evidence considered
- ClinVar: no entries found for NM_001122740.1:c.1661G>A across all search strategies.
Sources
BA1 The highest population allele frequency observed is 5.01×10⁻⁵ (0.005%, East Asian gnomAD v2.1), well below the 1% BA1 threshold for a stand-alone benign classification. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 highest subpopulation AF: EAS = 5.01e-05 (0.005%). gnomAD v4.1 highest: EAS = 4.46e-05. Both far below 1%.
Sources
BS1 The highest population allele frequency is 0.005% (gnomAD v2.1 East Asian), below the 0.3% BS1 threshold for a strong benign criterion. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpop AF: 5.01e-05 (0.005%). gnomAD v4.1 max subpop AF: 4.46e-05 (0.0045%). Both below 0.3%.
Sources
BS2 Only 2–3 alleles have been observed in gnomAD across all populations (total alleles surveyed: 282,762 in v2.1 and 1,614,058 in v4.1). This is insufficient observation in healthy adults to meet BS2, which requires the variant to be observed in multiple healthy individuals in a manner consistent with benign impact. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 2 total alleles (0 hom). gnomAD v4.1: 3 total alleles (0 hom). gnomAD-Canada: 0 alleles. Insufficient observations to conclude benign.
Sources
BS3 No well-established in vitro or in vivo functional studies have been identified that demonstrate no damaging effect for this variant. OncoKB lists 'Unknown Oncogenic Effect' and no variant-specific functional data. Details ▾Hide ▴
Evidence considered
- OncoKB: no variant-specific functional evidence. No literature PMIDs with functional data for p.Ser554Asn. BayesDel −0.538 and SpliceAI 0.0 are suggestive but do not constitute well-established functional studies.
Still missing
- No experimental functional studies for this variant.
Sources
BP1 ESR1 is not a gene where predominantly truncating variants are established as the sole cause of germline disease. The PVS1 gene context identifies literature supporting LOF mechanism but no well-characterized germline syndrome where missense variants can be dismissed via BP1. Details ▾Hide ▴
Evidence considered
- PVS1 gene context: LOF mechanism supported by targeted literature review
- but ESR1 lacks a CSPEC/VCEP framework and is not canonically recognized as a gene where only truncating variants cause germline disease. BP1 does not apply.
Sources
pvs1_gene_context
BP2 No observation of this variant in trans with a pathogenic variant for a recessive disorder, or in cis with a pathogenic variant for a dominant disorder, has been reported. Details ▾Hide ▴
Evidence considered
- No phase information available from ClinVar or gnomAD.
BP4 In silico evidence is mixed and does not reach the consensus required for BP4. BayesDel predicts benign (−0.538) and SpliceAI shows no splicing impact (max delta 0.0), but REVEL (0.213) is indeterminate. The evidence does not meet the 'multiple lines of computational evidence suggesting no impact' standard. Details ▾Hide ▴
Evidence considered
- BayesDel: −0.538 (benign). SpliceAI: max delta 0.0 (no splice effect). REVEL: 0.213 (indeterminate). Mixed signal
- insufficient for BP4.
Sources
BP5 No case has been identified in which this variant is present in a patient with an alternate molecular basis for disease (i.e., a co-occurring pathogenic variant explaining the phenotype). Details ▾Hide ▴
Evidence considered
- No co-occurrence data available from ClinVar or literature.
BP6 The variant is absent from ClinVar; no reputable source has classified it as benign. BP6 requires a classification from a source with supporting-level credibility. Details ▾Hide ▴
Evidence considered
- ClinVar: no entries. No clinical laboratory or expert panel classification exists.
Sources
Not assessed · 4 · no assessment recorded
PS4 No case-control or cohort prevalence data are available to assess enrichment of this variant in affected individuals versus controls. Details ▾Hide ▴
Still missing
- No case-control studies or cohort prevalence data identified.
PP4 No clinical phenotype information for the proband is available; cannot assess specificity of presentation for ESR1-related disease. Details ▾Hide ▴
Still missing
- No proband phenotype data provided.
BS4 No segregation or non-segregation data are available for this variant. Details ▾Hide ▴
Still missing
- No co-segregation analysis available.
PS5 No alternative variant at nucleotide position c.1661 with a different alternate allele has been classified as pathogenic in ClinVar. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar entirely
- no nucleotide-level comparator variants available.
Still missing
- No ClinVar entries at c.1661 for PS5 comparison.
Sources
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (p.Ser554Asn); PVS1 applies only to null variants (nonsense, frameshift, canonical splice ±1,2). Per ClinGen SVI PVS1 recommendations (PMC6185798), this variant does not fall into any eligible null-variant bucket. Details ▾Hide ▴
Evidence considered
- Variant class is missense substitution (c.1661G>A
- p.Ser554Asn)
- gene is PVS1-eligible but variant does not qualify.
Sources
PM5 N/AUnable to confirm classic same-residue PM5 semantics; no comparator variant at residue 554 with a different alternate amino acid and pathogenic classification was identified. Details ▾Hide ▴
Evidence considered
- Automated PM5 candidate harvesting returned no candidates. Residue 554 has no alternative pathogenic missense entries in ClinVar.
Sources
pm5_candidates
BP3 N/ASkipped: variant is a substitution, not an in-frame indel in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. This variant is missense (p.Ser554Asn), not synonymous. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- ESR1
- Transcript
- NM_001122740.1
- Coding (HGVS c.)
- NM_001122740.1:c.1661G>A
- Protein (HGVS p.)
- NP_001116212.1:p.(Ser554Asn)
- GRCh38
- chr6:152098839 G>A
- GRCh37
- chr6:152419974 G>A
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in ESR1
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
3 / 1,614,058 alleles
AF 1.86e-06 · 0 homozygotes · FAF 7.39e-06
gnomAD v2.1
2 / 282,762 alleles
AF 7.07e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,614,058 alleles · 0 hom · FAF 7.4e-06
| East Asian2 / 44,876 | 4.5e-05 |
| European (non-Finnish)1 / 1,180,034 | 8.5e-07 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 7.1e-06 · 2 / 282,762 alleles · 0 hom
| East Asian1 / 19,954 | 5e-05 |
| European (non-Finnish)1 / 129,082 | 7.7e-06 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.85867e-06; MAF= 0.00019%, 3/1614058 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 4.45673e-05; MAF= 0.00446%, 2/44876 alleles, homozygotes = 0); grpmax FAF= 7.39e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.07309e-06; MAF= 0.00071%, 2/282762 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.01153e-05; MAF= 0.00501%, 1/19954 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.213
- BayesDel
- -0.538
How the predictions were used
PP3 In silico tools do not support a deleterious effect: REVEL score 0.213 is in the indeterminate range (threshold for pathogenicity >0.5), BayesDel score −0.538 is negative (predicts benign), and SpliceAI max delta score is 0.0 (no predicted splicing impact). No HCI prior score is available for ESR1. Details ▾Hide ▴
Evidence considered
- REVEL: 0.213 (indeterminate). BayesDel: −0.538 (benign). SpliceAI: max delta 0.0 (no splice effect). HCI prior: gene not supported.
Sources
BP4 In silico evidence is mixed and does not reach the consensus required for BP4. BayesDel predicts benign (−0.538) and SpliceAI shows no splicing impact (max delta 0.0), but REVEL (0.213) is indeterminate. The evidence does not meet the 'multiple lines of computational evidence suggesting no impact' standard. Details ▾Hide ▴
Evidence considered
- BayesDel: −0.538 (benign). SpliceAI: max delta 0.0 (no splice effect). REVEL: 0.213 (indeterminate). Mixed signal
- insufficient for BP4.
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. This variant is missense (p.Ser554Asn), not synonymous. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.213. BayesDel score = -0.538498.
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
3 / 1,614,058 recorded alleles
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.1661G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/6-152419974-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr6-152098839-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/6-152098839-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001122740.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/ESR1/S554N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ESR1+c.1661G%3EA
- 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
This variant is present in gnomAD v4.1 (AF= 1.85867e-06; MAF= 0.00019%, 3/1614058 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 4.45673e-05; MAF= 0.00446%, 2/44876 alleles, homozygotes = 0); grpmax FAF= 7.39e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.07309e-06; MAF= 0.00071%, 2/282762 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.01153e-05; MAF= 0.00501%, 1/19954 alleles, homozygotes = 0).
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 = 0.213. BayesDel score = -0.538498.
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.