Submissions for variant NM_000059.4(BRCA2):c.6842G>A (p.Gly2281Glu)

dbSNP: rs80358908

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001188458	SCV001355526	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001555200	SCV001776574	uncertain significance	not provided	2022-09-22	criteria provided, single submitter	clinical testing	Observed in an individual with breast cancer (Deuitch et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7070G>A; Not observed at significant frequency in large population cohorts (gnomAD); In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 32884827)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001862979	SCV002187710	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2281 of the BRCA2 protein (p.Gly2281Glu). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 1 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs80358908, gnomAD 0.003%). 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: 926077). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change results in the activation of a cryptic splice site in 12 (PMID: 32046981). 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	RCV001188458	SCV002666666	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-15	criteria provided, single submitter	clinical testing	The c.6842G>A variant (also known as p.G2281E) is located in coding exon 11 of the BRCA2 gene. The glycine at codon 2281 is replaced by glutamic acid, an amino acid with similar properties. This change occurs in the first base pair of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. This alteration leads to increased but incomplete skipping of coding exon 11 (also known as exon 12 in the literature; Hujová P et al. Mol Biol Rep, 2019 Jun;46:2877-2884; Meulemans L et al. Cancer Res, 2020 04;80:1374-1386; Ambry internal data). Complete loss of coding exon 11 retains nearly 50% homology-directed DNA repair activity (Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). However, the clinical impact of loss of exon 11 and to what extent exon 11 is lost is uncertain as a different variant that results in incomplete skipping of coding exon 11 was identified in a compound heterozygous state in a patient without apparent Fanconi Anemia (Li L et al. Hum Mutat, 2009 Nov;30:1543-50). This suggests that exon 11 skipping may be dispensable for clinically relevant function at an unknown threshold of loss (Li L et al. Hum Mutat, 2009 Nov;30:1543-50; Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be inconclusive by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003389488	SCV004101683	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2281 of the BRCA2 protein (p.Gly2281Glu). Not observed at significant frequency in large population cohorts (gnomAD). In silico analysis supports that this missense variant does not alter protein structure/function. Observed in an individual with breast cancer (Deuitch et al., 2020). This variant is associated with the following publications: (PMID: 32884827).ClinVar contains an entry for this variant (Variation ID: 926077). This nucleotide position is highly conserved . Studies have shown that this missense change results in the activation of a cryptic splice site (PMID: 32046981). 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001555200	SCV005199809	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing