BRCA2 NM_000059.3:c.7970A>C, Lys2657Thr

The p.K2657T variant (also known as c.7970A>C), located in coding exon 16 of the BRCA2 gene, results from an A to C substitution at nucleotide position 7970. The lysine at codon 2657 is replaced by threonine, an amino acid with similar properties. This variant was non-functional in a homology-directed DNA repair (HDR) assay (Hu C et al. Am J Hum Genet. 2024 Mar;111(3):584-593). This alteration is also predicted to destabilize the local structure and disrupt the protein binding ability of BRCA2 (Yang H et al. Science 2002 Sep;297:1837-48; Marston NJ et al. Mol. Cell. Biol. 1999 Jul;19:4633-42; Ambry internal data) 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 majority of available evidence to date, this variant is likely to be pathogenic.

Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function. 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. ClinVar contains an entry for this variant (Variation ID: 441298). This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 2657 of the BRCA2 protein (p.Lys2657Thr). 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.