NM_007294.3:c.5073A>G (p.Thr1691=) is a synonymous variant at the penultimate base of BRCA1 exon 16, the -2 position of the canonical donor splice site, within the BRCT clinically important functional domain (aa 1650-1857).

PVS1 is met at moderate strength: the variant resides at a canonical donor splice site position (±1,2) and SpliceAI predicts a splice-altering effect (max delta 0.71).

PM2_Supporting is met: the variant is absent from gnomAD v2.1 and is observed as a single heterozygous allele in gnomAD v4.1 (1/1,607,416; AF 6.22e-07), consistent with a rare variant absent from population controls.

PP3 is met at supporting strength: SpliceAI predicts a splice-altering effect (max delta 0.71 ≥ 0.2), meeting the ENIGMA threshold for predicted splicing impact in silent variants.

No benign criteria are met. BP4 fails because SpliceAI delta (0.71) exceeds the ≤0.1 threshold for no predicted splicing impact. BP1_Strong does not apply because the variant is inside the BRCT domain and splicing is predicted. BS1 and BA1 thresholds are not reached at the observed allele frequency.

ENIGMA point total: PVS1_Moderate (+2) + PM2_Supporting (+1) + PP3 (+1) = 4, which falls within the VUS range (-1 to 5) per ENIGMA Table 3 combination rules.

The two PMIDs associated with this variant in ClinVar (30209399, 25394175) could not be verified at the variant level: full-text retrieval returned non-article content with no mention of c.5073A>G or p.Thr1691=.

This assessment requires human review: ENIGMA Table 4 should be consulted to confirm the exact PVS1 strength for exon 16 donor -2 splice variants, and functional mRNA studies should be sought to resolve the SpliceAI prediction. If mRNA studies confirm no aberrant splicing, PVS1 and PP3 would be negated and BP7 may become applicable, shifting classification toward benign.