NM_001122740.1:c.1150C>G (p.Leu384Val) is a missense variant in ESR1 exon 6. It is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 across all populations (PM2_Supporting).¹ Multiple in silico predictors support a deleterious effect: REVEL score 0.863 and BayesDel score 0.279 both exceed their respective pathogenicity thresholds (PP3_Supporting).² The variant is absent from ClinVar, COSMIC, and all population databases. No functional studies, case reports, cosegregation data, or de novo observations exist for this variant.³ PVS1 is not applicable as this is a missense variant that does not fall into the null-variant buckets per ClinGen SVI PVS1 recommendations (PMC6185798).⁴ This variant does not lie in a statistically significant mutational hotspot (cancerhotspots.org negative), and no pathogenic ClinVar variants cluster at residue Leu384. PM1 is not met.⁵ No publications were identified that mention NM_001122740.1:c.1150C>G. A targeted review of five ESR1 germline disease-context publications (PMID:15361840, PMID:25139996, PMID:41129222, PMID:22086303, PMID:26557847) confirmed none contain variant-specific evidence. Overall classification: Variant of Uncertain Significance (VUS). Two supporting-level pathogenic criteria (PM2_Supporting, PP3_Supporting) are met, which is insufficient to reach Likely Pathogenic under the generic ACMG/AMP 2015 classification rules (PMID:25741868). No benign criteria are met.⁶