Submissions for variant NM_000059.4(BRCA2):c.7874G>T (p.Arg2625Ile)

dbSNP: rs864622552

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487418	SCV000566886	uncertain significance	not provided	2015-06-10	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000802875	SCV000942722	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 2625 of the BRCA2 protein (p.Arg2625Ile). 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: 419217). 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: 35736817). 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.
Ambry Genetics	RCV002413321	SCV002680856	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-01-05	criteria provided, single submitter	clinical testing	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.
Color Diagnostics, LLC DBA Color Health	RCV002413321	SCV004362724	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-02	criteria provided, single submitter	clinical testing	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.
All of Us Research Program, National Institutes of Health	RCV004002293	SCV004845566	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-28	criteria provided, single submitter	clinical testing	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.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000802875	SCV005374644	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-02-15	criteria provided, single submitter	curation	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