BRCA2 NM_000059.3:c.7685T>G, Phe2562Cys

This missense variant replaces phenylalanine with cysteine at codon 2562 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have found the variant protein to be defective in homology-directed DNA repair assays in mammalian cells (PMID: 33609447, 35736817). This variant has been observed in an individual affected with autosomal recessive Fanconi anemia in trans with a pathogenic BRCA2 variant (ClinVar: SCV000187274.8). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The p.F2562C pathogenic mutation (also known as c.7685T>G), located in coding exon 15 of the BRCA2 gene, results from a T to G substitution at nucleotide position 7685. The phenylalanine at codon 2562 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been confirmed in trans with a BRCA2 pathogenic variant in an individual diagnosed with Fanconi anemia (Ambry internal data). This alteration was identified as non-functional in a homology-directed DNA repair (HDR) assay (Richardson ME et al. Am J Hum Genet. 2021 03;108(3):458-468). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi anemia, it is likely to 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.

This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 2562 of the BRCA2 protein (p.Phe2562Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 142784). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 33609447). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Published functional studies have shown that this variant has a deleterious effect on BRCA2 homology-directed DNA repair activity (PMIDs: 33609447 (2021) and 35736817 (2022)). Also, analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.