About ESR1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ESR1 c.1235G>A, p.(Arg412Lys)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM1Moderate
PM1 · moderate
Residue 412 (Arg) lies within the ESR1 ligand-binding domain (LBD; residues 305–552 of the canonical isoform), a well-established critical functional domain required for estrogen binding and receptor transactivation. The variant is absent from population databases, consistent with absence of benign variation at this position.
PM2Moderate
PM2 · moderate
Absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes and genomes), and gnomAD-Canada v1.0 (genomes), with allele frequency of 0% across all populations, well below the PM2 threshold of <0.1%.
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: PM1 moderate, PM2 moderate; combination = 2 moderate, 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
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. 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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV105067291, n = 1 times).
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: 2 met · 11 not met · 10 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
This missense variant (c.1235G>A, p.Arg412Lys) lies within the ESR1 ligand-binding domain (LBD, residues 305–552), a critical functional domain required for estrogen binding and receptor transactivation (PM1).
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, with an allele frequency of 0% across all populations (PM2).
No functional studies assessing the effect of p.Arg412Lys on ESR1 activity were identified; PS3 is not met.
Computational evidence is inconsistent: REVEL score 0.487 is borderline, BayesDel score 0.300 is indeterminate, and SpliceAI predicts no splicing impact (max delta 0.01); PP3 is not met and BP4 is not met.
The variant is absent from ClinVar, with no pathogenic or benign assertions from any submitter; PS5, PP5, and BP6 are not met.
No published literature reporting this specific variant was identified; PS1, PS2, PS3, PS4, PM6, PP1, and PP4 could not be assessed due to absence of variant-specific clinical or functional data.
With only PM1 (moderate) and PM2 (moderate) met, the variant does not reach the Likely Pathogenic threshold per generic ACMG/AMP 2015 combination rules (PMID:25741868), which require at least 3 moderate criteria or 1 strong criterion for Likely Pathogenic.
This variant is classified as a Variant of Uncertain Significance (VUS) per generic ACMG/AMP 2015 framework.
No criteria match.
Met · 2
PM1 ModerateResidue 412 (Arg) lies within the ESR1 ligand-binding domain (LBD; residues 305–552 of the canonical isoform), a well-established critical functional domain required for estrogen binding and receptor transactivation. The variant is absent from population databases, consistent with absence of benign variation at this position. Details ▾Hide ▴
Evidence considered
- Residue 412 is in the ESR1 ligand-binding domain (LBD)
- a critical functional domain. Variant absent from all gnomAD populations.
Still missing
- No ESR1 VCEP exists to provide official domain-based PM1 specifications
- reliance on generic ACMG LBD domain assignment.
Sources
PM2 ModerateAbsent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes and genomes), and gnomAD-Canada v1.0 (genomes), with allele frequency of 0% across all populations, well below the PM2 threshold of <0.1%. Details ▾Hide ▴
Evidence considered
- AF=0 in gnomAD v2.1 (AC=0)
- gnomAD v4.1 (AC=0)
- and gnomAD-Canada v1.0 (AC=0).
Still missing
- Coverage at this position in gnomAD was not explicitly returned but absence across three independent cohorts supports true rarity.
Sources
Not met · 11 · evaluated, threshold not reached
PS3 No well-established in vitro or in vivo functional studies demonstrating a damaging effect of p.Arg412Lys on ESR1 protein function were identified. Details ▾Hide ▴
Evidence considered
- OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence.
Still missing
- No luciferase reporter
- transactivation
- or ligand-binding assay data available for p.Arg412Lys.
Sources
PS4 The variant is absent from population databases and no case-control study demonstrating statistically significant enrichment in affected individuals versus controls was identified. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada. No case-control data available.
Still missing
- No case-control or association study comparing variant frequency in affected vs. general population.
Sources
PM5 No pathogenic missense variant at the same residue (Arg412) with a different amino acid change was identified in ClinVar. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvesting returned zero same-residue comparator variants
- recommendation level is 'not_applicable'.
Still missing
- No alternative amino acid substitution at Arg412 known to be pathogenic.
Sources
pm5_candidates
PP3 Multiple lines of computational evidence are inconsistent and do not converge to support a deleterious effect: REVEL score 0.487 is below the commonly applied 0.5 pathogenic threshold, BayesDel score 0.300 is in an indeterminate range, and SpliceAI predicts no splicing impact (max delta score 0.01). Details ▾Hide ▴
Evidence considered
- REVEL=0.487 (borderline
- below 0.5 threshold)
- BayesDel=0.300 (indeterminate)
- SpliceAI max delta=0.01 (no splicing impact).
Sources
PP5 No reputable source has recently reported this variant as pathogenic. The variant is absent from ClinVar under the queried transcript NM_001122740.1. Details ▾Hide ▴
BA1 Allele frequency is 0% in gnomAD v2.1, v4.1, and gnomAD-Canada, far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- AF=0% across all gnomAD populations.
Sources
BS1 Allele frequency is 0% in all population databases, far below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- AF=0% across all gnomAD populations.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect of p.Arg412Lys on ESR1 protein function were identified. Details ▾Hide ▴
Evidence considered
- No functional studies demonstrating neutral effect identified.
Still missing
- No functional characterization of p.Arg412Lys available.
BP4 Multiple lines of in silico evidence are inconsistent or indeterminate and do not converge to support a benign effect: REVEL 0.487 is borderline (below the typical 0.5 pathogenic threshold but not clearly benign), BayesDel 0.300 is in an indeterminate range, and SpliceAI predicts no splicing impact (max delta 0.01). Evidence is insufficient to meet BP4. Details ▾Hide ▴
Evidence considered
- REVEL=0.487 (borderline/indeterminate)
- BayesDel=0.300 (indeterminate)
- SpliceAI max delta=0.01 (no splicing impact).
Sources
BP6 No reputable source has recently reported this variant as benign. The variant is absent from ClinVar under the queried transcript NM_001122740.1. Details ▾Hide ▴
PS5 No pathogenic missense variant at the same codon (Arg412) with a different amino acid change was identified to support PS5. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned zero same-residue comparator variants in ClinVar.
Still missing
- No known pathogenic variants at codon 412.
Sources
pm5_candidates
Not assessed · 10 · no assessment recorded
PS1 No alternate nucleotide change at codon 412 (Arg) with a known pathogenic classification was identified in ClinVar or literature to support PS1. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no same-amino-acid pathogenic comparator identified.
Still missing
- No alternate nucleotide change at Arg412 identified in any database.
Sources
PS2 No confirmed de novo occurrence with maternity and paternity confirmation has been reported for this variant in the literature or public databases. Details ▾Hide ▴
Evidence considered
- No de novo data found in literature
- ClinVar
- or exploratory search.
Still missing
- No trio or de novo sequencing data available for ESR1 c.1235G>A.
PM6 No de novo observation without confirmation of paternity and maternity has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data identified in literature or databases.
Still missing
- No reported de novo events for ESR1 c.1235G>A.
PP1 No co-segregation data with disease in multiple affected family members are available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation or family linkage data identified.
Still missing
- No family studies or kindred data including ESR1 c.1235G>A.
PP2 HCI prior score is not available for ESR1, precluding assessment of whether the gene has a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
- HCI prior not found for ESR1
- gene not in the HCI supported gene list.
Still missing
- No HCI prior or equivalent metric to assess constraint against missense variation in ESR1.
PP4 No patient phenotype or family history data are available for this variant to assess whether the clinical presentation is highly specific for ESR1-related disease. Details ▾Hide ▴
Evidence considered
- No clinical phenotype or family history information available.
Still missing
- No proband phenotype or clinical indication provided.
BS2 No data are available regarding observation of this variant in healthy adults for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- No healthy adult carrier data identified.
Still missing
- No population-based healthy cohort screening data for ESR1 c.1235G>A.
BS4 No segregation data demonstrating lack of association with disease (e.g., unaffected individuals carrying the variant in multiple family members) are available. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family studies with unaffected carriers.
BP1 The primary disease mechanism for germline ESR1 variants is not well-established. While literature suggests some support for loss-of-function as a mechanism, there is insufficient evidence that primarily truncating variants cause ESR1-related disease to apply BP1 without a CSPEC/VCEP specification. Details ▾Hide ▴
Evidence considered
- pvs1_gene_context supports LoF as a possible mechanism (literature-based
- not CSPEC-confirmed)
- but insufficient to establish that truncating variants are the primary cause.
Still missing
- No official CSPEC/VCEP confirmation of disease mechanism or variant spectrum for ESR1.
Sources
pvs1_gene_context
BP5 No data are available regarding an alternate molecular basis for disease in a patient carrying this variant. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis data available.
Still missing
- No patient-level data to assess for an alternate molecular cause.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.1235G>A, p.Arg412Lys) and does not fall into the default generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense substitution
- variant_bucket 'other'
- apply_generic_pvs1_framework is false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP2 N/AESR1-associated disorders are not known to follow autosomal recessive inheritance; BP2 applies only when a variant is observed in trans with a pathogenic variant for a fully penetrant recessive disorder. Details ▾Hide ▴
Evidence considered
- ESR1 is not associated with a recessive disorder.
BP3 N/ABP3 applies to in-frame deletions/insertions in a repetitive region without a known function; this variant is a single-nucleotide substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies only to synonymous variants without predicted splice impact; this is a missense variant (p.Arg412Lys). Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous.
Identifiers
- Gene
- ESR1
- Transcript
- NM_001122740.1
- Coding (HGVS c.)
- NM_001122740.1:c.1235G>A
- Protein (HGVS p.)
- NP_001116212.1:p.(Arg412Lys)
- GRCh38
- chr6:152011794 G>A
- GRCh37
- chr6:152332929 G>A
- COSMIC
- COSV105067291
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
- 0.487
- BayesDel
- 0.300
How the predictions were used
PP3 Multiple lines of computational evidence are inconsistent and do not converge to support a deleterious effect: REVEL score 0.487 is below the commonly applied 0.5 pathogenic threshold, BayesDel score 0.300 is in an indeterminate range, and SpliceAI predicts no splicing impact (max delta score 0.01). Details ▾Hide ▴
Evidence considered
- REVEL=0.487 (borderline
- below 0.5 threshold)
- BayesDel=0.300 (indeterminate)
- SpliceAI max delta=0.01 (no splicing impact).
Sources
BP4 Multiple lines of in silico evidence are inconsistent or indeterminate and do not converge to support a benign effect: REVEL 0.487 is borderline (below the typical 0.5 pathogenic threshold but not clearly benign), BayesDel 0.300 is in an indeterminate range, and SpliceAI predicts no splicing impact (max delta 0.01). Evidence is insufficient to meet BP4. Details ▾Hide ▴
Evidence considered
- REVEL=0.487 (borderline/indeterminate)
- BayesDel=0.300 (indeterminate)
- SpliceAI max delta=0.01 (no splicing impact).
Sources
BP7 N/ABP7 applies only to synonymous variants without predicted splice impact; this is a missense variant (p.Arg412Lys). Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.487. BayesDel score = 0.299838.
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 0.010
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_001122740.1%3Ac.1235G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/6-152332929-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr6-152011794-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/6-152011794-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001122740.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/ESR1/R412K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=162576891
- 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 = 0.01). REVEL score = 0.487. BayesDel score = 0.299838.
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 previously been reported in somatic cancers (COSMIC; COSV105067291, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.