NM_007294.3:c.83T>C (p.Leu28Pro) is a missense variant in BRCA1 exon 3, located within the RING domain (aa 2-101), a clinically important functional domain per ENIGMA specifications.

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

In silico analysis predicts a deleterious effect: BayesDel no-AF score of 0.451556 exceeds the ENIGMA PP3 threshold of 0.28 for predicted damaging protein impact, and REVEL score is 0.832. SpliceAI predicts no splicing impact (max delta 0.00). These findings meet ENIGMA PP3 at Supporting strength.

BP4 is not met because the BayesDel score (0.451556) exceeds the ENIGMA benign prediction threshold of 0.15.

The variant is classified as Uncertain Significance (VUS) in ClinVar by the ENIGMA expert panel (ClinVar ID 55732), with 6 clinical laboratories reporting VUS and 1 reporting Likely Pathogenic.

Functional evidence (PS3/BS3) could not be assessed: ENIGMA Table 9 does not list c.83T>C, OncoKB classifies the effect as Inconclusive, and no publication abstract confirmed variant-specific functional data. The variant lies within the RING domain targeted by saturation genome editing studies (Findlay 2018, Starita 2015) but full-text verification is needed.

Clinical evidence (PP4/BP5 via Li et al. 2020 clinical history LR; PP1/BS4 via cosegregation) could not be assessed due to unavailability of variant-level data in the extracted materials.