NM_007294.4:c.4450T>G (p.Ser1484Ala) is a missense variant in BRCA1 exon 13, located outside all ENIGMA-defined clinically important functional domains (between the coiled-coil domain at aa 1391-1424 and the BRCT domain at aa 1650-1857).

The variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting). However, read depth at this position should be confirmed via gnomAD screenshots to ensure the absence is not artifactual.

BP1_Strong is met: the variant is a missense substitution outside all three BRCA1 clinically important functional domains, and SpliceAI predicts no splicing impact (max delta = 0.03).

No functional assay data (PS3/BS3) are available for p.Ser1484Ala in ENIGMA calibrated assays. The only codon-1484 variant with functional data is c.4450T>A (p.Ser1484Thr, BS3_Strong), but this evidence does not transfer to the Ala substitution.

ClinVar reports this variant as Uncertain Significance (3 clinical laboratories, criteria provided, single submitter). No expert panel classification is available.

No co-segregation (PP1/BS4), case-control (PS4), or clinical-history likelihood ratio (PP4/BP5) data are available for this variant.

Applying ENIGMA v1.2.0 Table 3 combining rules: the criteria evidence yields BP1_Strong (1 Strong Benign) + PM2_Supporting (1 Supporting Pathogenic). With one Strong Benign and one Supporting Pathogenic, the evidence is conflicting. Per ENIGMA Table 3, neither the benign nor the likely benign combination thresholds are met: a single Strong Benign criterion alone is insufficient for Likely Benign without an accompanying Supporting Benign or Moderate Benign. The classification remains Uncertain Significance (VUS).