ClinVar

Description

The c.594_597delTGTG variant, located in coding exon 8 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 594 to 597, causing a translational frameshift with a predicted alternate stop codon (p.S198Rfs*35). This alteration was identified in a compound heterozygous state with another pathogenic BRCA1 alteration in a patient with features that were consistent with Fanconi Anemia including increased chromosome breakage upon DNA damage. Cells from this patient had numerous defects including reduced BRCA1 and RAD51 foci formation and ultrasensitivity to PARP inhibitors. These defects were rescued by a partial BRCA1 transgene to a level comparable to a sibling whose cells had only one BRCA1 alteration. This suggests that these defects are due specifically to BRCA1 deficiency (Sawyer SL et al. Cancer Discov, 2015 Feb;5:135-42). Alterations that result in premature protein truncation are typically deleterious in nature; however, this alteration occurs in one of the exons that is absent in a predominant, in-frame, naturally occurring isoform (Δ7_8, also known as Δ9,10 in the literature) and is likely to be spliced out in this normal isoform that produces a partially functional protein (Colombo M et al. Hum. Mol. Genet. 2014 Jul;23:3666-80; Whiley PJ et al. Clin. Chem. 2014 Feb;60:341-52), Therefore, the effect of this variant in a heterozygous state may be hypomorphic. Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, because this variant is identified in one or more patients with Fanconi Anemia it 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 BRCA1 alteration. As risk estimates are unknown at this time, clinical correlation is advised.