ClinVar

Description

The c.67+3A>C intronic variant results from an A to C substitution 3 nucleotides after coding exon 1 in the BRCA2 gene. 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration at this location impacting the same donor site (c.67+3A>G) has also been reported to cause the skipping of coding exon 1 (described as exon 2 in the literature; Parsons MT et al. Mol Carcinog 2015 Jul;54(7):513-22) and has been detected in a compound heterozygous state with another pathogenic variant in an individual with Fanconi anemia (Feben C. et al. Fam Cancer 2017 07;16(3):441-446). Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, because a similar variant observed to have the same splicing impact as this alteration is identified in one or more patients with Fanconi Anemia, this alteration may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.