Submissions for variant NM_000059.4(BRCA2):c.8275G>C (p.Val2759Leu)

gnomAD frequency: 0.00001  dbSNP: rs1320594065

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001027352	SCV001189893	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-06	criteria provided, single submitter	clinical testing	The p.V2759L variant (also known as c.8275G>C), located in coding exon 17 of the BRCA2 gene, results from a G to C substitution at nucleotide position 8275. The valine at codon 2759 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001050995	SCV001215128	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-03-10	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2759 of the BRCA2 protein (p.Val2759Leu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 827550). 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 with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV001027352	SCV001358069	uncertain significance	Hereditary cancer-predisposing syndrome	2019-07-09	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 2759 of the BRCA2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/248674 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV001776092	SCV002012635	uncertain significance	not provided	2020-02-05	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as c.8503G>C
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492212	SCV004240362	uncertain significance	Breast and/or ovarian cancer	2023-05-25	criteria provided, single submitter	clinical testing