This missense variant (c.1235G>A, p.Arg412Lys) lies within the ESR1 ligand-binding domain (LBD, residues 305–552), a critical functional domain required for estrogen binding and receptor transactivation (PM1).1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, with an allele frequency of 0% across all populations (PM2).2 No functional studies assessing the effect of p.Arg412Lys on ESR1 activity were identified; PS3 is not met.3 Computational evidence is inconsistent: REVEL score 0.487 is borderline, BayesDel score 0.300 is indeterminate, and SpliceAI predicts no splicing impact (max delta 0.01); PP3 is not met and BP4 is not met.4 The variant is absent from ClinVar, with no pathogenic or benign assertions from any submitter; PS5, PP5, and BP6 are not met.5 No published literature reporting this specific variant was identified; PS1, PS2, PS3, PS4, PM6, PP1, and PP4 could not be assessed due to absence of variant-specific clinical or functional data. With only PM1 (moderate) and PM2 (moderate) met, the variant does not reach the Likely Pathogenic threshold per generic ACMG/AMP 2015 combination rules (PMID:25741868), which require at least 3 moderate criteria or 1 strong criterion for Likely Pathogenic.6 This variant is classified as a Variant of Uncertain Significance (VUS) per generic ACMG/AMP 2015 framework.7
ESR1
Final classification
VUS
ESR1 c.1235G>A · p.Arg412Lys
ESR1
This missense variant (c.1235G>A, p.Arg412Lys) lies within the ESR1 ligand-binding domain (LBD, residues 305–552), a critical functional domain required for estrogen binding and receptor transactivation (PM1).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate; combination = 2 moderate, which maps to VUS.
Classification rationale
PM1PM2
VUS
ESR1 c.1235G>A
PM1 + PM2
→
VUS
3
oncokb ↗
4
revelbayesdelspliceai ↗
6
generic_acmg_combination_rules
7
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 · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
moderate
review
Pathogenic
Residue 412 (Arg) lies within the ESR1 ligand-binding domain (LBD; residues 305–552 of the canonical isoform), a well-established critical functional domain required for estrogen binding and receptor transactivation. The variant is absent from population databases, consistent with absence of benign variation at this position.
Residue 412 is in the ESR1 ligand-binding domain (LBD)a critical functional domain. Variant absent from all gnomAD populations.
✓
PM2
moderate
Pathogenic
Absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes and genomes), and gnomAD-Canada v1.0 (genomes), with allele frequency of 0% across all populations, well below the PM2 threshold of <0.1%.
AF=0 in gnomAD v2.1 (AC=0)gnomAD v4.1 (AC=0)and gnomAD-Canada v1.0 (AC=0).
Assessed · not applied
Pathogenic
PS1
No alternate nucleotide change at codon 412 (Arg) with a known pathogenic classification was identified in ClinVar or literature to support PS1.
PS2
No confirmed de novo occurrence with maternity and paternity confirmation has been reported for this variant in the literature or public databases.
PS3
No well-established in vitro or in vivo functional studies demonstrating a damaging effect of p.Arg412Lys on ESR1 protein function were identified.
PS4
The variant is absent from population databases and no case-control study demonstrating statistically significant enrichment in affected individuals versus controls was identified.
PM5
No pathogenic missense variant at the same residue (Arg412) with a different amino acid change was identified in ClinVar.
PM6
No de novo observation without confirmation of paternity and maternity has been reported for this variant.
PP1
No co-segregation data with disease in multiple affected family members are available for this variant.
PP2
HCI prior score is not available for ESR1, precluding assessment of whether the gene has a low rate of benign missense variation.
PP3
Multiple lines of computational evidence are inconsistent and do not converge to support a deleterious effect: REVEL score 0.487 is below the commonly applied 0.5 pathogenic threshold, BayesDel score 0.300 is in an indeterminate range, and SpliceAI predicts no splicing impact (max delta score 0.01).
PP4
No patient phenotype or family history data are available for this variant to assess whether the clinical presentation is highly specific for ESR1-related disease.
PP5
No reputable source has recently reported this variant as pathogenic.
Benign
BA1
Allele frequency is 0% in gnomAD v2.1, v4.1, and gnomAD-Canada, far below the BA1 threshold of >1%.
BS1
Allele frequency is 0% in all population databases, far below the BS1 threshold of >0.3%.
BS2
No data are available regarding observation of this variant in healthy adults for a fully penetrant dominant disorder.
BS3
No well-established in vitro or in vivo functional studies demonstrating no damaging effect of p.Arg412Lys on ESR1 protein function were identified.
BS4
No segregation data demonstrating lack of association with disease (e.g., unaffected individuals carrying the variant in multiple family members) are available.
BP1
The primary disease mechanism for germline ESR1 variants is not well-established.
BP4
Multiple lines of in silico evidence are inconsistent or indeterminate and do not converge to support a benign effect: REVEL 0.487 is borderline (below the typical 0.5 pathogenic threshold but not clearly benign), BayesDel 0.300 is in an indeterminate range, and SpliceAI predicts no splicing impact (max delta 0.01).
BP5
No data are available regarding an alternate molecular basis for disease in a patient carrying this variant.
BP6
No reputable source has recently reported this variant as benign.
N/A · 4
PVS1 · BP2 · BP3 · 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 = 0.01). REVEL score = 0.487. BayesDel score = 0.299838.
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 previously been reported in somatic cancers (COSMIC; COSV105067291, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links