BRCA2 NM_000059.3:c.6859A>T, Arg2287Ter

The p.R2287* variant (also known as c.6859A>T), located in coding exon 11 of the BRCA2 gene, results from an A to T substitution at nucleotide position 6859. This changes the amino acid from an arginine to a stop codon within coding exon 11. This variant has been confirmed to be in trans with a BRCA2 pathogenic variant in an individual diagnosed with clinical features of Fanconi anemia (external communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, this variant occurs in an exon that is absent in biologically relevant transcripts (referred to as exon 12 in the literature; Li L et al. Hum. Mutat. 2009 Nov;30(11):1543-50). Of note, however, one study reported that this alteration did not significantly impact the expression of transcripts skipping CDS11 (exon 12) in RNA studies, and was shown to have reduced complementation of Brca2 loss and homology directed repair activity in mESC--based functional assays (Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, because this variant has been 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.

ClinVar contains an entry for this variant (Variation ID: 575178). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2287*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.

The BRCA2 c.6859A>T (p.Arg2287*) variant is predicted to cause the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in an individual with myeloid neoplasia (PMID: 36266327 (2020)). A published functional study indicates that this variant is damaging to BRCA2 protein function (PMID: 32046981 (2020)). The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is consistent with pathogenicity. Based on the available information, this variant is classified as likely pathogenic.