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.1 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.2 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.3 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).4
ESR1
Final classification
VUS
ESR1 c.173C>T · p.Ala58Val
ESR1
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.
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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
ESR1 c.173C>T
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_001122740.1 · variants mapped to exon structure
ESR1
NM_001122740.1
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1Absent from gnomAD v4.1Absent from gnomAD-Canada v1.0
✓
BP4
supporting
Benign
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 score 0.092 (benignbelow 0.5 threshold)BayesDel score -0.418 (benign
Assessed · not applied
Pathogenic
PS2
No de novo data available for this variant.
PS3
No functional data exists for NM_001122740.1:c.173C>T (p.A58V).
PS4
No case-control or statistical evidence of enrichment in affected individuals.
PM1
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).
PM6
No de novo data available.
PP1
No segregation data available.
PP2
PP2 requires the gene to have a low rate of benign missense variation and missense variants to be a common disease mechanism.
PP3
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).
PP4
No proband phenotype or clinical indication is provided in the case materials.
PP5
No reputable source (clinical diagnostic laboratory, expert panel) has classified this variant as pathogenic.
Benign
BA1
The variant is absent from all population databases (gnomAD v2.1, v4.1, Canada).
BS1
The variant is absent from all population databases.
BS2
The variant has not been observed in any population database, so there is no evidence of observation in healthy adults.
BS3
No functional studies have been performed on this variant demonstrating no deleterious effect.
BS4
No segregation data available to demonstrate lack of cosegregation with disease in affected family members.
BP2
No observation data available regarding trans configuration with a pathogenic variant.
BP5
No information is available regarding an alternative molecular basis for disease in the proband.
BP6
No reputable source classifies this variant as benign.
N/A · 5
PVS1 · PS1 · PM5 · BP1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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 = 0.00). REVEL score = 0.092. BayesDel score = -0.418096.
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