NM_000059.4:c.425G>A (p.Ser142Asn) is a missense variant in BRCA2 exon 4, located outside the established clinically important functional domains (PALB2-binding domain aa 10-40; DNA-binding domain aa 2481-3186).¹ This variant is absent from gnomAD v2.1 but present in gnomAD v4.1 in 44 of 1,544,990 alleles (AF=0.00285%), including 1 homozygote, with a grpmax filter allele frequency of 0.024% (0.00024125). The highest subpopulation frequency is in the South Asian population (30/89,438 alleles, AF=0.034%).² SpliceAI predicts a splicing alteration with a maximum delta score of 0.91, exceeding the ENIGMA PP3 threshold of ≥0.2 for missense variants, supporting a potential splice effect (PP3_Supporting). However, the specific SpliceAI sub-scores (donor gain/loss, acceptor gain/loss) are not available, and no RNA splicing assay has been performed to confirm this prediction.³ The population frequency evidence meets ENIGMA BS1 at Supporting strength: the grpmax FAF of 0.00024125 exceeds the 0.01% threshold, and the observation of a homozygous individual in gnomAD v4.1 argues against high-penetrance pathogenicity. The variant is absent from gnomAD v2.1 per the ENIGMA-specified dataset, but the larger v4.1 release confirms population presence.⁴ Multifactorial likelihood analysis from Parsons et al. 2019 (PMID:31131967) yields a combined LR of 1.383 (neutral), with segregation LR=1.554 and pathology LR=0.89. Neither PP1 (co-segregation) nor BS4 (lack of segregation) thresholds are met. The clinical-history LR from Li et al. 2020 (PMID:31853058) is 1.027 (1 proband, neutral zone); PP4 and BP5 are not met.⁵ The variant is not listed in ENIGMA Table 9 for calibrated functional assay results (PS3/BS3 not assessed). No variant-specific functional evidence was identified in the literature or in OncoKB.⁶ In ClinVar, this variant is classified as Uncertain Significance by 4 clinical laboratories, as Likely Pathogenic by 3, and as Pathogenic by 2 (ClinVar Variation ID: 197099), with review status of criteria provided, single submitter and no expert panel classification.⁷ Under the ENIGMA BRCA1/2 v1.2.0 combining rules (Table 3): PP3_Supporting (1 pathogenic supporting) and BS1_Supporting (1 benign supporting) are the only met criteria. Neither Likely Pathogenic nor Likely Benign thresholds are reached. The variant is classified as a Variant of Uncertain Significance (VUS).⁸