BRCA1 NM_007294.3:c.101C>T, Pro34Leu

The p.P34L variant (also known as c.101C>T), located in coding exon 2 of the BRCA1 gene, results from a C to T substitution at nucleotide position 101. The proline at codon 34 is replaced by leucine, an amino acid with similar properties. One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

The c.101C>T variant in BRCA1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 34 (p.Pro34Leu). This variant is present in gnomAD v4.1 but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This BRCA1 missense variant is within a key functional domain and a SpliceAI score of 0.01 predicts no impact on splicing (score threshold ≤0.1). The computational predictor BayesDel (noAF) gives a score of 0.45, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change (PP3 met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMID:30209399, 35659930, 37168384) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 5.47 (based on Case-Control LR=5.47), within the thresholds for moderate evidence towards pathogenicity (LR ≥4.3 & <18.7) (PP4_Moderate met; PMID: 40413188). In summary, this variant meets the criteria to be classified as a Likely Pathogenic for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PP3, PS3, PP4_Moderate).