Variant classification summary

NM_001122740.1:c.173C>T

ESR1 · NP_001116212.1:p.(Ala58Val) · NM_001122740.1

GRCh37: chr6:152129220 C>T · GRCh38: chr6:151808085 C>T

Gene: ESR1 Transcript: NM_001122740.1

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

ESR1

Transcript

NM_001122740.1

Protein

NP_001116212.1:p.(Ala58Val)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001122740.1:c.173C>T (p.Ala58Val) in ESR1 is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying PM2 at supporting strength.

2

Multiple in silico tools predict a benign effect: REVEL score 0.092, BayesDel score -0.418, and SpliceAI max delta 0.00. These concordant benign predictions satisfy BP4 at supporting benign strength.

3

No functional data, segregation data, de novo reports, case-control studies, or ClinVar classifications exist for this variant. All other assessed criteria are either not met or not applicable.

4

The evidence is conflicting: one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) result in indeterminate classification. Under generic ACMG/AMP 2015 combination rules, this variant is classified as 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	This is a missense variant (c.173C>T, p.Ala58Val). PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice consensus). The variant falls into the 'other' bucket per ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No pathogenic variant at codon 58 (p.Ala58) with a different nucleotide change has been reported in ClinVar. PS1 requires an established pathogenic variant at the same amino acid position.	clinvar
PS2	Not met	No de novo data available for this variant. No publications or ClinVar submissions report de novo occurrence of NM_001122740.1:c.173C>T.	clinvar
PS3	Not met	No functional data exists for NM_001122740.1:c.173C>T (p.A58V). OncoKB reports unknown oncogenic effect. No literature describes experimental characterization of this variant or a systematically characterized range that includes residue 58.	oncokb
PS4	Not met	No case-control or statistical evidence of enrichment in affected individuals. The variant is absent from all population databases, precluding prevalence comparison.	gnomad_v2 gnomad_v4 clinvar
PS5	N/A	No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar entirely, and no clinical laboratory has reported it as pathogenic. PS5 requires a prior pathogenic assertion by a reputable source.	clinvar
PM1	Not met	The p.A58V substitution lies in the N-terminal AF-1 domain of ESR1, but this position is not a statistically significant mutational hotspot (cancerhotspots.org negative). Without an established germline disease-associated mutational hotspot or a defined functional domain where pathogenic missense variants are enriched in ESR1 germline disease, PM1 is not met.
PM2	Met	NM_001122740.1:c.173C>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes + genomes), and gnomAD-Canada v1.0. Per generic ACMG/AMP guidelines, absence from population databases at an allele frequency below 0.1% qualifies as PM2 at supporting strength.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic missense variant at the same amino acid position (p.Ala58) has been identified. The PM5 candidate search returned zero same-residue comparator variants in ClinVar.	pm5_candidates clinvar
PM6	Not met	No de novo data available. No publications or ClinVar submissions report de novo occurrence of this variant. Without confirmed maternity/paternity, PM6 cannot be applied.	clinvar
PP1	Not met	No segregation data available. No family studies or cosegregation analysis has been reported for this variant.
PP2	Not assessed	PP2 requires the gene to have a low rate of benign missense variation and missense variants to be a common disease mechanism. No HCI prior or missense constraint data (e.g., gnomAD Z-score) is available for ESR1. The gene is not a well-established germline disease gene, so the missense constraint profile cannot be reliably evaluated.
PP3	Not met	Multiple in silico tools predict a benign effect: REVEL score 0.092 (below 0.5 threshold), BayesDel score -0.418 (below 0.0 threshold), SpliceAI max delta 0.0 (no splice impact). No computational tool supports a damaging prediction.	revel bayesdel spliceai
PP4	Not assessed	No proband phenotype or clinical indication is provided in the case materials. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. Without phenotype data, this criterion cannot be evaluated.
PP5	Not met	No reputable source (clinical diagnostic laboratory, expert panel) has classified this variant as pathogenic. The variant is absent from ClinVar entirely.	clinvar
BA1	Not met	The variant is absent from all population databases (gnomAD v2.1, v4.1, Canada). The allele frequency is 0%, far below the 1% threshold required for BA1.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all population databases. The allele frequency is 0%, below the 0.3% threshold required for BS1. Absence does not satisfy BS1; a population frequency greater than expected for the disorder is required.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	The variant has not been observed in any population database, so there is no evidence of observation in healthy adults. BS2 requires confirmed observation in a healthy adult individual for a fully penetrant disorder.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies have been performed on this variant demonstrating no deleterious effect. OncoKB reports unknown oncogenic effect with no variant-specific functional evidence.	oncokb
BS4	Not met	No segregation data available to demonstrate lack of cosegregation with disease in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants cause disease. ESR1 is not established as a gene where the sole disease mechanism is loss-of-function via truncation. In somatic cancer, activating missense mutations in ESR1 are well-characterized.
BP2	Not met	No observation data available regarding trans configuration with a pathogenic variant. The variant is absent from population databases, and no clinical reports describe compound heterozygosity.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. REVEL score 0.092 is well below the 0.5 threshold for damaging prediction. BayesDel score -0.418 is below the 0.0 threshold for deleterious prediction. SpliceAI max delta score is 0.00, predicting no splice alteration. Per generic ACMG/AMP guidelines, concordant benign predictions from multiple in silico tools support BP4 at supporting benign strength.	revel bayesdel spliceai
BP5	Not assessed	No information is available regarding an alternative molecular basis for disease in the proband. BP5 requires a confirmed alternate molecular cause for the observed phenotype.
BP6	Not met	No reputable source classifies this variant as benign. The variant is absent from ClinVar entirely; no diagnostic laboratory or expert panel has issued a benign classification.	clinvar
BP7	N/A	BP7 is reserved for synonymous (silent) variants with no predicted splice impact. NM_001122740.1:c.173C>T is a missense variant producing p.Ala58Val, not a synonymous variant.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.