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.1 In silico analysis with REVEL predicts a deleterious effect (score 0.916), providing supporting evidence for pathogenicity (PP3).2 Population frequency data from gnomAD v2.1 and v4.1 is unavailable due to technical limitations; gnomAD-Canada reports the variant as absent.3 No functional studies, family segregation data, or clinical case reports were identified for this variant in the literature or curated databases.4 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).5
ESR1
Final classification
VUS
ESR1 c.1519C>T · p.Leu507Phe
ESR1
NM_001122740.1:c.1519C>T (p.Leu507Phe) is a missense variant in exon 8 of ESR1, encoding the estrogen receptor alpha.
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.
Classification rationale
PP3
VUS
ESR1 c.1519C>T
PP3
→
VUS
Gene diagram
· NM_001122740.1 · variants mapped to exon structure
ESR1
NM_001122740.1
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 22 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PP3
supporting
Pathogenic
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).
REVEL score 0.916 (pathogenic)BayesDel score 0.456 (intermediate)SpliceAI max delta 0.01 (no splicing impact).
Assessed · not applied
Pathogenic
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.
PS2
No de novo data or family studies are available for this variant in the case materials.
PS3
No functional studies of NM_001122740.1:c.1519C>T (p.Leu507Phe) were identified in the literature or curated databases.
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.
PM1
p.Leu507Phe lies within the ligand-binding domain (LBD) of ESR1, a well-characterized functional domain.
PM2
gnomAD v2.1 and v4.1 population frequency data is unavailable due to scraping timeout.
PM5
No other pathogenic missense variant at codon 507 (Leu507) was identified in ClinVar.
PM6
No de novo or family segregation data is available for this variant in the case materials or literature.
PP1
No co-segregation data is available for this variant.
PP2
gnomAD constraint data is unavailable (scraping timeout), preventing assessment of the rate of benign missense variation in ESR1.
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.
PP5
This variant is absent from ClinVar.
Benign
BA1
This variant is absent from available population databases; allele frequency does not exceed the BA1 threshold of >1%.
BS1
gnomAD v2.1 and v4.1 population frequency data is unavailable due to scraping timeout.
BS2
No data is available on observation of this variant in healthy adult individuals for a fully penetrant disorder.
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.
BS4
No family segregation data is available to support lack of segregation in affected family members.
BP1
ESR1-related disease is not primarily caused by truncating variants.
BP2
No phase data (in trans or in cis with other pathogenic variants) is available for this variant.
BP4
REVEL score of 0.916 strongly predicts a deleterious effect, contradicting the absence of functional impact.
BP5
No data is available on an alternate molecular basis for disease in cases with this variant.
BP6
This variant is absent from ClinVar.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
v4.1
This variant is absent from gnomAD v4.1.
v2.1
This variant is absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links