ClinVar

Description

The p.W2626C pathogenic mutation (also known as c.7878G>T), located in coding exon 16 of the BRCA2 gene, results from a G to T substitution at nucleotide position 7878. The tryptophan at codon 2626 is replaced by cysteine, an amino acid with highly dissimilar properties. Functional assays evaluating homology-directed DNA break repair (HDR), embryonic stem cell rescue viability, susceptibility to DNA damaging agents, chromosomal aberration, and RAD51 foci have all indicated deficient function for BRCA2 p.W2626C mutants (Biswas K et al. Blood 2011 Sep;118:2430-42; Guidugli L et al. Cancer Res 2013 Jan;73:265-75; Hendriks G et al. Hum Mutat 2014 Nov;35:1382-91; Guidugli L et al. Am J Hum Genet 2018 Jan; Mesman RLS et al. Genet Med, 2018 Jul). A close match (c.7878G>C) that results in the same predicted protein impact (p.W2626C) has been identified in unrelated Fanconi anemia patients, including confirmed in trans with a pathogenic BRCA2 alteration in one patient (Wagner JE et al. Blood 2004 Apr;103:3226-9; Kopic S et al. Acta Paediatr 2011 May;100:780-3). A family history weighting algorithm has described c.7878G>C to be hypomorphic (Pruss D et al. Breast Cancer Res Treat, 2014 Aug;147:119-32). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. However, because this amino acid change has been 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 BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.