BRCA2 NM_000059.3:c.8375T>C, Leu2792Pro

Data used in classification: The frequency of this variant is 0/138,632 individuals (tgnomAD) (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (23.4) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the BRCA2 Homology-Directed Repair Activity assay for the DNA Binding Domain (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of 1.0 (PS3_strong). Data not used in classification: There are additional reports of this variant in ClinVar (1), BIC (1), and BRCA2 LOVD (1).

The p.L2792P variant (also known as c.8375T>C), located in coding exon 18 of the BRCA2 gene, results from a T to C substitution at nucleotide position 8375. The leucine at codon 2792 is replaced by proline, an amino acid with similar properties. This alteration is non-functional in multiple assays including a homology-directed, DNA repair assay and multiple drug sensitivity assays (Guidugli L et al. Am. J. Hum. Genet., 2018 Feb;102:233-248; Hart SN et al. Genet. Med., 2019 01;21:71-80; Ikegami M et al. Nat Commun, 2020 May;11:2573; Richardson ME et al. Am J Hum Genet, 2021 Mar;108:458-468). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.

Variant summary: BRCA2 c.8375T>C (p.Leu2792Pro) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251416 control chromosomes. To our knowledge, no occurrence of c.8375T>C in individuals affected with BRCA2-related conditions has been reported. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of normal homology directed repair activity in vitro (HDR assay) (Guidugli_2018, Hu_2024). The following publications have been ascertained in the context of this evaluation (PMID: 19043619, 29394989, 39402389, 23108138, 39375938, 38417439, 37725113, 37067535, 33503928, 32042831, 30583724, 29884841, 24323938, 23108138, 18724707, 19043619, 18403564). ClinVar contains an entry for this variant (Variation ID: 52568). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 19043619, 23108138, 29394989). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRCA2 protein function. ClinVar contains an entry for this variant (Variation ID: 52568). 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 replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2792 of the BRCA2 protein (p.Leu2792Pro).