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.1 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.2 No ClinVar entries exist for this variant; no functional studies, segregation data, or case-control data are available.3 PVS1 is not applicable: this is a missense variant that does not meet null-variant criteria per PMC6185798.4 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).5
ESR1
Final classification
VUS
ESR1 c.970C>A · p.Pro324Thr
ESR1
NM_001122740.1:c.970C>A (p.Pro324Thr) is a missense variant in exon 5 of ESR1.
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.
Classification rationale
PM2PP3
VUS
ESR1 c.970C>A
PM2 + PP3
→
VUS
2
revelbayesdel
5
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 · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1 (0 alleles)absent from gnomAD v4.1 (0 alleles)absent from gnomAD-Canada v1.0 (0 alleles).
✓
PP3
supporting
Pathogenic
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).
REVEL: 0.844 (damaging)BayesDel noAF: 0.302 (damaging per -0.36 threshold)SpliceAI: max delta 0.00 (no predicted splice impact).
Assessed · not applied
Pathogenic
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.
PS2
No de novo observation with confirmed paternity and maternity is available for this variant.
PS3
No functional studies directly testing NM_001122740.1:c.970C>A (p.Pro324Thr) or a systematically characterized range including residue 324 were identified.
PS4
No case-control or prevalence data comparing affected individuals to controls is available for this variant.
PM1
Residue Pro324 is not located in a statistically significant cancer hotspot per cancerhotspots.org.
PM5
No pathogenic missense variant at the same amino acid residue (Pro324) was identified for comparison.
PM6
No de novo observation (without confirmation of paternity and maternity) is available for this variant.
PP1
No co-segregation data with disease in multiple affected family members is available for this variant.
PP2
Insufficient data to establish that ESR1 has a low rate of benign missense variation with missense variants as a common disease mechanism.
PP4
No patient phenotype or family history data specific to the disease gene was provided for assessment.
PP5
This variant is absent from ClinVar and no reputable source (including 3-star expert panel) has classified it as pathogenic.
Benign
BA1
This variant is absent from all gnomAD population databases; allele frequency of 0% does not exceed the BA1 threshold of >1%.
BS1
This variant is absent from all gnomAD population databases; allele frequency of 0% does not exceed the BS1 threshold of >0.3%.
BS2
No data on homozygous or hemizygous observations of this variant in healthy adults are available.
BS3
No functional studies demonstrating a neutral or benign effect for NM_001122740.1:c.970C>A (p.Pro324Thr) were identified.
BS4
No segregation data in affected family members demonstrating lack of co-segregation with disease is available.
BP1
ESR1 is not a gene where only truncating variants cause disease.
BP2
No data on observation of this variant in trans with a known pathogenic dominant variant are available.
BP4
Multiple lines of computational evidence do not support a benign impact.
BP5
No data demonstrating that this variant is consistently absent in individuals with ESR1-related disease are available.
BP6
This variant is absent from ClinVar and no reputable source (including 3-star expert panel) has classified it as benign.
N/A · 2
PVS1 · 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 = 0.844. BayesDel score = 0.301677.
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