Submissions for variant NM_000059.4(BRCA2):c.6233G>T (p.Gly2078Val)

gnomAD frequency: 0.00001  dbSNP: rs769883812

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484329	SCV000570117	uncertain significance	not provided	2016-04-28	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.6233G>T at the cDNA level, p.Gly2078Val (G2078V) at the protein level, and results in the change of a Glycine to a Valine (GGA>GTA). Using alternate nomenclature, this variant would be defined as BRCA2 6461G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gly2078Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Gly2078Val occurs at a position that is conserved in mammals and is located within the BRC8 domain and the RAD51 binding domain (Cole 2011, Roy 2012). In silico analyses predict that this variant is probably damaging to protein structure and function, and multiple splicing models predict that this variant may create a cryptic splice donor site for exon 11 and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA2 Gly2078Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000821918	SCV000962692	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-04	criteria provided, single submitter	clinical testing	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. 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 not expected to disrupt BRCA2 protein function. ClinVar contains an entry for this variant (Variation ID: 421039). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (rs769883812, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2078 of the BRCA2 protein (p.Gly2078Val).
Color Diagnostics, LLC DBA Color Health	RCV001184327	SCV001350282	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-20	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 2078 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/248494 chromosomes 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.
Ambry Genetics	RCV001184327	SCV002656383	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-22	criteria provided, single submitter	clinical testing	The p.G2078V variant (also known as c.6233G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 6233. The glycine at codon 2078 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001184327	SCV003852339	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV004802068	SCV005424523	uncertain significance	BRCA2-related cancer predisposition	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 2078 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/248494 chromosomes 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.