NM_007294.4:c.4450T>G (p.Ser1484Ala) is a missense variant in BRCA1 exon 13 located at amino acid position 1484, outside all ENIGMA-defined clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT repeats aa 1650-1857). SpliceAI predicts no splicing impact (max delta 0.03).

This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting ENIGMA PM2_Supporting.

The variant meets ENIGMA BP1_Strong: missense variant outside a clinically important functional domain with no predicted splicing impact (SpliceAI max delta 0.03 ≤0.1).

This variant is not listed in ENIGMA Table9 (curated functional assays) or ST4 (functional assay results) for either PS3 or BS3. The related variant c.4450T>A (p.Ser1484Thr) has BS3_Strong with 'No functional impact,' but this is a different amino acid substitution and does not constitute direct evidence for p.Ser1484Ala.

No case-control, segregation, or clinical-history likelihood ratio data were identified for this specific variant. It is not listed in the Li et al. 2020 (PMID:31853058) clinical-history LR table; c.4450T>A is listed with neutral LR=1.066.

In ClinVar, this variant is classified as Uncertain Significance by three clinical laboratories (ClinVar ID 630099). No expert panel classification is available.

Under the ENIGMA Table 3 all_of combination rules, one Strong Benign criterion (BP1_Strong) with no qualifying Supporting Benign or Moderate Benign criterion does not meet the Likely Benign threshold (requires Strong Benign + Supporting Benign or Strong Benign + Moderate Benign). The conflicting PM2_Supporting (pathogenic direction) further precludes a benign or likely benign classification. The variant remains a Variant of Uncertain Significance.