ClinVar

Description

The c.316+5G>C intronic pathogenic mutation results from a G to C substitution 5 nucleotides after coding exon 2 in the BRCA2 gene. This alteration has been reported in multiple families with hereditary breast and/or ovarian cancer and segregates strongly with disease (Caputo SM et al. Oncotarget 2018 Apr;9(25):17334-17348; Labidi-Galy SI et al. Clin. Cancer Res. 2018 Jan;24(2):326-333). Using the HSF, MaxEnt, and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site. RNA analyses using both patient RNA samples and minigene assays have shown that this alteration causes complete skipping of coding exon 2 (also designated as exon 3 in published literature) (Ambry internal data; Bonnet C et al. J. Med. Genet. 2008 Jul;45(7):438-46; Houdayer C et al. Hum. Mutat. 2012 Aug;33(8):1228-38; Fraile-Bethencourt E et al. J. Pathol., 2019 Aug;248:409-420), and further functional analysis showed that cells with this alteration could not survive upon Mitomycin-C treatment, which corresponds to a lack of function for the BRCA2 protein with the c.316+5G>C alteration (Caputo SM et al. Oncotarget 2018 Apr;9(25):17334-17348). Based on the majority of available evidence to-date, this alteration is interpreted as a disease-causing mutation.