Submissions for variant NM_000059.4(BRCA2):c.7676C>G (p.Ser2559Cys)

dbSNP: rs1060502421

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473973	SCV000549592	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2559 of the BRCA2 protein (p.Ser2559Cys). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 409479). 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.
Ambry Genetics	RCV001026696	SCV001189126	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-09	criteria provided, single submitter	clinical testing	The p.S2559C variant (also known as c.7676C>G), located in coding exon 15 of the BRCA2 gene, results from a C to G substitution at nucleotide position 7676. The serine at codon 2559 is replaced by cysteine, 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001764422	SCV002008202	uncertain significance	not provided	2021-07-21	criteria provided, single submitter	clinical testing	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 7904C>G; This variant is associated with the following publications: (PMID: 12228710, 27535533)
Color Diagnostics, LLC DBA Color Health	RCV001026696	SCV002052514	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 2559 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). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in an individual affected with breast cancer (PMID: 32231682). 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.
Baylor Genetics	RCV003476086	SCV004211834	uncertain significance	Familial cancer of breast	2023-10-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000811	SCV004844454	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 2559 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). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in an individual affected with breast cancer (PMID: 32231682). 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.