ClinVar

Description

The c.516G>A variant (also known as p.K172K), located in coding exon 5 of the BRCA2 gene, results from a G to A substitution at nucleotide position 516. This nucleotide substitution does not change the at codon 172. This alteration was identified in a Danish patient with breast cancer diagnosed at 37 and 65 years old; her family history was significant for male breast cancer in her father and ovarian cancer in a paternal aunt (Hansen TV et al. Breast Cancer Res. Treat. 2010 Feb;119:547-50). This alteration was detected in a patient with urothelial cancer (Bertelsen B et al. NPJ Genom Med, 2019 Jun;4:13). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). However, this change occurs in the last base pair of coding exon 5, which makes it likely to have some effect on normal mRNA splicing. Splicing assays have shown this variant to result in nonsense-mediated decay prone transcripts that lack coding exons 4 and 5 (Ambry internal data; Hansen TV et al. Breast Cancer Res. Treat. 2010 Feb;119:547-50). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.