ClinVar Genomic variation as it relates to human health

This variant is denoted BRCA2 c.7874G>T at the cDNA level, p.Arg2625Ile (R2625I) at the protein level, and results in the change of an Arginine to an Isoleucine (AGA>ATA). Using alternate nomenclature, this variant would be defined as BRCA2 8102G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Arg2625Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Arg2625Ile occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located in the DNA-binding domain (Borg 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA2 Arg2625Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.

This sequence change replaces arginine with isoleucine at codon 2625 of the BRCA2 protein (p.Arg2625Ile). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and isoleucine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 419217). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (ExAC no frequency).

The p.R2625I variant (also known as c.7874G>T), located in coding exon 16 of the BRCA2 gene, results from a G to T substitution at nucleotide position 7874. The arginine at codon 2625 is replaced by isoleucine, an amino acid with similar properties. This variant was non-functional in a homology-directed DNA repair (HDR) assay (Ambry internal data). In addition, this variant was reported in 2/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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 well 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.

This missense variant replaces arginine with isoleucine at codon 2625 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 shown that this variant impairs homology-directed DNA repair (PMID: 33609447). This variant has been reported in an individual affected with prostate cancer (PMID: 31874108). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008629). 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.

This missense variant replaces arginine with isoleucine at codon 2625 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 shown that this variant impairs homology-directed DNA repair (PMID: 33609447). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 1/53461 unaffected controls (p-value=1; Leiden Open Variation Database DB-ID BRCA2_008629) (PMID: 33471991). 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.

According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose these criteria: PS3 (strong pathogenic): ClinGen BRCA2 Table 9: Richardson 2021 (PMID:33609447) - Damaging, PM2 (supporting pathogenic): not in gnomAD