NM_007294.3:c.1233T>G (p.Asp411Glu) is a missense variant in BRCA1 exon 10, classified as Benign by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel (ClinVar Variation ID: 41804).

This variant is present in gnomAD v2.1 at 12/282,222 alleles (AF=4.25e-05) with a grpmax filter allele frequency of 0.024% (0.00024454) in the African/African American subpopulation (11/24,934 alleles), exceeding the ENIGMA BS1_Strong threshold of >0.01%.

ENIGMA Table 9 (v1.2.0) assigns BS3_Strong to this variant based on calibrated functional assay evidence from Bouwman et al. 2020 (PMID:32546644), demonstrating protein function in homologous recombination repair complementation similar to benign control variants.

Codon 411 is located outside all three (potentially) clinically important functional domains defined by ENIGMA for BRCA1: RING finger (aa 2-101), coiled-coil (aa 1391-1424), and BRCT repeats (aa 1650-1857). SpliceAI predicts no splicing impact (max delta score 0.07). These findings satisfy ENIGMA BP1_Strong criteria.

Parsons et al. 2019 multifactorial likelihood analysis (PMID:31131967) reports a combined LR of 1.29, a segregation LR of 1.93, and a family history LR of 6.48 for this variant. The combined LR is in the neutral range and does not independently support either pathogenic (PP4) or benign (BP5) classification.

No evidence was found to support any pathogenic criterion. PVS1, PS1, PS2, PS3, PS4, PS5, PM1, PM2, PM5, PM6, PP1, PP2, PP3, PP4, and PP5 are all either not met or not applicable.

Under the ENIGMA Table 3 combination rules, two or more Strong Benign criteria support a Benign classification. The three Strong Benign criteria met (BS1_Strong, BS3_Strong, BP1_Strong) satisfy the Benign classification threshold.