ClinVar

Description

This pathogenic variant is denoted BRCA2 c.7007G>A at the cDNA level. Located at the last nucleotide of exon 13, this variant disrupts a natural splice donor site, and multiple functional studies have found this variant to result in skipping of exon 13 (Thomassen 2006, Sanz 2010, Biswas 2011). Although the nucleotide substitution results in the change of an Arginine to a Histidine at codon 2336, and is called Arg2336His in the literature, we are using only the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than a resulting missense variant. This variant, also denoted 7235G>A using alternate nomenclature, has been identified in both male and female breast cancer patients as well as in the compound heterozygous state or homozygous state in at least five individuals with Fanconi Anemia (Howlett 2002, Alter 2007, Machackova 2008, Ahmad 2012, Coppa 2014, Degrolard-Courcet 2014, Bu 2016, Ghazwani 2016). BRCA2 c.7007G>A was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The nucleotide which is altered, a guanine (G) at base 7007, is conserved through mammals. Based on current evidence, we consider this variant to be pathogenic.