NM_001122740.1:c.1519C>T

ESR1 · NP_001116212.1:p.(Leu507Phe) · NM_001122740.1

GRCh37: chr6:152415669 C>T · GRCh38: chr6:152094534 C>T

Gene: ESR1 Transcript: NM_001122740.1

Final call

VUS

PP3 supporting

Variant details

Gene

ESR1

Transcript

NM_001122740.1

Protein

NP_001116212.1:p.(Leu507Phe)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

In silico analysis with REVEL predicts a deleterious effect (score 0.916), providing supporting evidence for pathogenicity (PP3).

Population frequency data from gnomAD v2.1 and v4.1 is unavailable due to technical limitations; gnomAD-Canada reports the variant as absent.

No functional studies, family segregation data, or clinical case reports were identified for this variant in the literature or curated databases.

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_001122740.1:c.1519C>T is a missense substitution (p.Leu507Phe), not a null variant (nonsense, frameshift, or canonical ±1,2 splice). Generic PVS1 framework (PMC6185798) requires a null-type variant; this variant is in the 'other' bucket.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	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.	clinvar
PS2	Not assessed	No de novo data or family studies are available for this variant in the case materials.
PS3	Not met	No functional studies of NM_001122740.1:c.1519C>T (p.Leu507Phe) were identified in the literature or curated databases. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence.	oncokb
PS4	Not met	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.	clinvar
PS5	Not met	No previously established pathogenic variant with the same amino acid change (p.Leu507Phe) was identified in ClinVar or the literature.	clinvar
PM1	Not met	p.Leu507Phe lies within the ligand-binding domain (LBD) of ESR1, a well-characterized functional domain. However, this residue is not a statistically significant hotspot at cancerhotspots.org, and the missense variant does not demonstrably remove or truncate the domain. Without either hotspot evidence or functional data confirming domain disruption, PM1 is not met for a missense variant.
PM2	Not assessed	gnomAD v2.1 and v4.1 population frequency data is unavailable due to scraping timeout. gnomAD-Canada v1.0 reports the variant as absent, but this dataset alone is insufficient to establish population absence at the confidence required for PM2.	gnomad_canada
PM5	Not met	No other pathogenic missense variant at codon 507 (Leu507) was identified in ClinVar. The PM5 candidate search returned zero same-residue comparator variants.	pm5_candidates clinvar
PM6	Not assessed	No de novo or family segregation data is available for this variant in the case materials or literature.
PP1	Not met	No co-segregation data is available for this variant.
PP2	Not assessed	gnomAD constraint data is unavailable (scraping timeout), preventing assessment of the rate of benign missense variation in ESR1. Without constraint metrics, PP2 cannot be securely applied.
PP3	Met	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 bayesdel spliceai
PP4	Not assessed	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	Not met	This variant is absent from ClinVar. No reputable clinical source has reported it as pathogenic.	clinvar
BA1	Not met	This variant is absent from available population databases; allele frequency does not exceed the BA1 threshold of >1%.	gnomad_canada
BS1	Not assessed	gnomAD v2.1 and v4.1 population frequency data is unavailable due to scraping timeout. Without the primary population databases, the allele frequency cannot be compared to the BS1 threshold of >0.3%.
BS2	Not met	No data is available on observation of this variant in healthy adult individuals for a fully penetrant disorder.
BS3	Not met	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.	oncokb
BS4	Not met	No family segregation data is available to support lack of segregation in affected family members.
BP1	Not met	ESR1-related disease is not primarily caused by truncating variants. Missense variants in the ligand-binding domain are a well-documented mechanism in hormone-resistant breast cancer.	oncokb
BP2	Not met	No phase data (in trans or in cis with other pathogenic variants) is available for this variant.
BP4	Not met	REVEL score of 0.916 strongly predicts a deleterious effect, contradicting the absence of functional impact. Although SpliceAI shows no splicing impact (max delta 0.01), the strong REVEL prediction precludes application of BP4.	revel spliceai bayesdel
BP5	Not met	No data is available on an alternate molecular basis for disease in cases with this variant.
BP6	Not met	This variant is absent from ClinVar. No reputable clinical source has reported it as benign.	clinvar
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a single-nucleotide substitution.
BP7	N/A	NM_001122740.1:c.1519C>T is a missense variant (p.Leu507Phe), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact.
PM3	N/A	PM3 requires identification of the variant in trans with a pathogenic variant for recessive disorders; no trans-phase data is available for this autosomal gene.
PM4	N/A	PM4 applies to non-repeat protein length changes (in-frame deletions/insertions, stop-loss); this is a missense substitution.

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