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