0%
ESR1c.970C>AUncertain significance
Print report
Variant interpretation report

ESR1 c.970C>A, p.(Pro324Thr)

NM_001122740.1:c.970C>A NP_001116212.1:p.(Pro324Thr) 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

This variant is absent from all gnomAD population databases (v2.1 exomes, v4.1 exomes, and gnomAD-Canada v1.0 genomes), meeting the PM2 threshold of <0.1% allele frequency.

PP3Supporting
PP3 · supporting

Multiple lines of in silico computational evidence support a deleterious effect. REVEL score of 0.844 falls well above the damaging threshold (>0.5). BayesDel noAF score of 0.302 is above the -0.36 damaging threshold, providing additional in silico support. SpliceAI predicts no splicing impact (max delta 0.00).

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.

26 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_001122740.1:c.970C>A (p.Pro324Thr) is a missense variant in exon 5 of ESR1.

This variant is absent from gnomAD population databases (v2.1, v4.1, and gnomAD-Canada), meeting PM2 at supporting strength.

Computational evidence supports a deleterious effect: REVEL score 0.844 (damaging) and BayesDel noAF score 0.302 (above the -0.36 damaging threshold), meeting PP3 at supporting strength.

No ClinVar entries exist for this variant; no functional studies, segregation data, or case-control data are available.

PVS1 is not applicable: this is a missense variant that does not meet null-variant criteria per PMC6185798.

With only two supporting pathogenic criteria (PM2, PP3) and no benign criteria met, this variant is classified as a Variant of Uncertain Significance (VUS) per generic ACMG/AMP 2015 combination rules (PMID:25741868).

Met · 2

PM2 SupportingThis variant is absent from all gnomAD population databases (v2.1 exomes, v4.1 exomes, and gnomAD-Canada v1.0 genomes), meeting the PM2 threshold of <0.1% allele frequency. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles)
  • absent from gnomAD v4.1 (0 alleles)
  • absent from gnomAD-Canada v1.0 (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingMultiple lines of in silico computational evidence support a deleterious effect. REVEL score of 0.844 falls well above the damaging threshold (>0.5). BayesDel noAF score of 0.302 is above the -0.36 damaging threshold, providing additional in silico support. SpliceAI predicts no splicing impact (max delta 0.00). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.844 (damaging)
  • BayesDel noAF: 0.302 (damaging per -0.36 threshold)
  • SpliceAI: max delta 0.00 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗

Not met · 22 · evaluated, threshold not reached

PS1 No known pathogenic variant causing the same amino acid change (Pro324Thr) via a different nucleotide substitution has been identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no same-amino-acid comparator available.
Still missing
  • No ClinVar entries or literature reports of any Pro324 amino acid change.
Sources
clinvar ↗
PS2 No de novo observation with confirmed paternity and maternity is available for this variant. Details ▾Hide ▴
Still missing
  • No de novo testing or family study data available.
PS3 No functional studies directly testing NM_001122740.1:c.970C>A (p.Pro324Thr) or a systematically characterized range including residue 324 were identified. OncoKB reports Unknown Oncogenic Effect. Computational prediction alone (REVEL 0.844) does not satisfy PS3 experimental evidence requirements. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional data
  • no systematic range characterization covering residue 324.
Still missing
  • No functional assay data for this variant or the Pro324 residue.
Sources
oncokb ↗
PS4 No case-control or prevalence data comparing affected individuals to controls is available for this variant. Details ▾Hide ▴
Still missing
  • No case-control or cohort studies reporting this variant.
PM1 Residue Pro324 is not located in a statistically significant cancer hotspot per cancerhotspots.org. Although ESR1 position 324 lies within the ligand-binding domain (aa 302–552), no domain-level functional evidence was identified in the case materials to support PM1 application per generic ACMG 2015 criteria. Details ▾Hide ▴
Evidence considered
  • cancerhotspots.org: residue not significant
  • no domain-specific literature supporting PM1 was identified.
Still missing
  • No domain-level mutational or functional data supporting PM1 for the ESR1 LBD in a germline context.
PM5 No pathogenic missense variant at the same amino acid residue (Pro324) was identified for comparison. Automated PM5 candidate harvesting returned zero candidates. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: 0 same-residue candidates
  • 0 expert panel P/LP candidates.
Still missing
  • No ClinVar entries at Pro324 for PM5 comparison.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation (without confirmation of paternity and maternity) is available for this variant. Details ▾Hide ▴
Still missing
  • No de novo reports in the literature or databases.
PP1 No co-segregation data with disease in multiple affected family members is available for this variant. Details ▾Hide ▴
Still missing
  • No family co-segregation data available.
PP2 Insufficient data to establish that ESR1 has a low rate of benign missense variation with missense variants as a common disease mechanism. gnomAD missense constraint metrics (Z-score) are not available in the case materials. Details ▾Hide ▴
Still missing
  • No gnomAD missense constraint Z-score or ClinGen gene-level PP2 assessment available for ESR1.
PP4 No patient phenotype or family history data specific to the disease gene was provided for assessment. Details ▾Hide ▴
Still missing
  • Patient phenotype and family history were not provided.
PP5 This variant is absent from ClinVar and no reputable source (including 3-star expert panel) has classified it as pathogenic. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar with zero submissions.
Sources
clinvar ↗
BA1 This variant is absent from all gnomAD population databases; allele frequency of 0% does not exceed the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • v4.1
  • and gnomAD-Canada
  • allele frequency = 0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 This variant is absent from all gnomAD population databases; allele frequency of 0% does not exceed the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • v4.1
  • and gnomAD-Canada
  • allele frequency = 0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No data on homozygous or hemizygous observations of this variant in healthy adults are available. Details ▾Hide ▴
Still missing
  • No homozygous or hemizygous observation data in healthy controls.
BS3 No functional studies demonstrating a neutral or benign effect for NM_001122740.1:c.970C>A (p.Pro324Thr) were identified. Details ▾Hide ▴
Still missing
  • No functional assay data demonstrating no damaging effect.
BS4 No segregation data in affected family members demonstrating lack of co-segregation with disease is available. Details ▾Hide ▴
Still missing
  • No family segregation data available.
BP1 ESR1 is not a gene where only truncating variants cause disease. Published evidence (PMID:41129222) suggests rare regulatory and potentially coding alleles of ESR1 may contribute to inherited breast cancer predisposition, indicating missense variants may be disease-relevant. Details ▾Hide ▴
Evidence considered
  • ESR1 disease mechanism is not restricted to truncating variants
  • regulatory and missense alleles implicated (PMID:41129222).
BP2 No data on observation of this variant in trans with a known pathogenic dominant variant are available. Details ▾Hide ▴
Still missing
  • No trans-phase observation data available.
BP4 Multiple lines of computational evidence do not support a benign impact. REVEL score of 0.844 and BayesDel score of 0.302 both predict a deleterious effect. SpliceAI predicts no splicing impact (max delta 0.00) but this alone does not outweigh the damaging missense predictions. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.844 (damaging)
  • BayesDel: 0.302 (damaging)
  • computational consensus supports deleterious effect
  • not benign.
Sources
revelbayesdelspliceai ↗
BP5 No data demonstrating that this variant is consistently absent in individuals with ESR1-related disease are available. Details ▾Hide ▴
Still missing
  • No case series or cohort studies comparing affected vs. unaffected individuals.
BP6 This variant is absent from ClinVar and no reputable source (including 3-star expert panel) has classified it as benign. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar with zero submissions.
Sources
clinvar ↗
PS5 No alternate pathogenic variant at the same residue (Pro324) has been identified in ClinVar or the literature to support PS5. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no same-residue pathogenic comparators identified.
Still missing
  • No ClinVar entries at Pro324 position.
Sources
clinvar ↗
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution (c.970C>A, p.Pro324Thr) and does not fall into the ClinGen SVI PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Details ▾Hide ▴
Evidence considered
  • Missense variant in exon 5
  • variant_bucket classification is 'other'
  • apply_generic_pvs1_framework: false per PMC6185798.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP7 N/AThis variant is a missense substitution (c.970C>A, p.Pro324Thr), not a synonymous variant; BP7 applies exclusively to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Variant type is missense
  • not synonymous.

Identifiers

Gene
ESR1
Transcript
NM_001122740.1
Coding (HGVS c.)
NM_001122740.1:c.970C>A
Protein (HGVS p.)
NP_001116212.1:p.(Pro324Thr)
GRCh38
chr6:151944382 C>A
GRCh37
chr6:152265517 C>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…
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 -88 bp
0.000
SpliceAI acceptor gainat -209 bp
0.000
SpliceAI donor lossat -25 bp
0.000
SpliceAI donor gainat +19 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.844
BayesDel
0.302

How the predictions were used

PP3 SupportingMultiple lines of in silico computational evidence support a deleterious effect. REVEL score of 0.844 falls well above the damaging threshold (>0.5). BayesDel noAF score of 0.302 is above the -0.36 damaging threshold, providing additional in silico support. SpliceAI predicts no splicing impact (max delta 0.00). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.844 (damaging)
  • BayesDel noAF: 0.302 (damaging per -0.36 threshold)
  • SpliceAI: max delta 0.00 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗
BP4 Multiple lines of computational evidence do not support a benign impact. REVEL score of 0.844 and BayesDel score of 0.302 both predict a deleterious effect. SpliceAI predicts no splicing impact (max delta 0.00) but this alone does not outweigh the damaging missense predictions. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.844 (damaging)
  • BayesDel: 0.302 (damaging)
  • computational consensus supports deleterious effect
  • not benign.
Sources
revelbayesdelspliceai ↗
BP7 N/AThis variant is a missense substitution (c.970C>A, p.Pro324Thr), not a synonymous variant; BP7 applies exclusively to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Variant type is missense
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.844. BayesDel score = 0.301677.

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 = 0.844. BayesDel score = 0.301677.

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.