ClinVar

Description

The BRCA2 p.Leu2999Leu variant was shown to have no effect on exon 23 splicing in a functional assay using hybrid minigene construction (Sanz 2010). In addition, a well-validated bioinformatics model applying information theory for splicing mutation analysis of BRCA1 and BRCA2 variants complemented this finding with the result of no concordant splicing effect (Mucaki 2010). The variant was also identified in dbSNP (ID: rs80359804) as “With Uncertain significance allele”, Clinvitae database (classifications: likely benign and uncertain significance), the ClinVar database (with conflicting interpretations of pathogenicity, classified as likely benign by Invitae and Ambry Genetics, and uncertain significance by BIC), the BIC database (1x with unknown clinical importance), UMD (3x with a ”unclassified variant” classification); in the NHLBI GO Exome Sequencing Project in 2 of 8590 European American alleles, (frequency: 0.00023), and the Exome Aggregation Consortium database (March 14, 2016) in 3 of 121072 chromosomes (freq. 0.00002), specifically in the Euorpean (Non-Finnish) population in 3 of 66564 chromosomes (freq.0.000045), but not in African, East Asian, Finnish, Latino, other and South Asian populations, increasing the likelihood this could be a low frequency benign variant. The p.Leu2999Leu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.