BRCA2 NM_000059.3:c.8164A>G, Thr2722Ala

The p.T2722A variant (also known as c.8164A>G), located in coding exon 17 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8164. The threonine at codon 2722 is replaced by alanine, an amino acid with similar properties. This variant was non-functional in a homology-directed DNA repair (HDR) assay (Richardson ME et al. Am J Hum Genet, 2021 03;108:458-468; Hu C et al. Clin Cancer Res. 2022 Sep;28(17):3742-3751). Two saturation genome editing-based studies, including a haploid cell-survival assay and a humanized mouse embryonic stem cell line assay of drug response and survival, demonstrate that this nucleotide substitution is non-functional (Huang H et al. Nature. 2025 Feb;638(8050):528-537; Sahu S et al. Nature. 2025 Feb;638(8050):538-545). 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 variant is likely to be pathogenic.

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Thr2722 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12145750, 18607349, 23108138, 25146914). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2722 of the BRCA2 protein (p.Thr2722Ala). 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: 479367). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA2 function. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 33609447).