Submissions for variant NM_000059.4(BRCA2):c.2558A>G (p.Gln853Arg)

dbSNP: rs56245590

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130947	SCV000185860	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-23	criteria provided, single submitter	clinical testing	The p.Q853R variant (also known as c.2558A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 2558. The glutamine at codon 853 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CSER _CC_NCGL, University of Washington	RCV000211539	SCV000212196	uncertain significance	Hereditary breast ovarian cancer syndrome	2015-03-11	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001212	SCV001158373	uncertain significance	not specified	2019-04-16	criteria provided, single submitter	clinical testing	The BRCA2 c.2558A>G; p.Gln853Arg variant (rs56245590), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 142112). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glutamine at codon 853 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000211539	SCV001231085	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-12-31	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: 142112). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 853 of the BRCA2 protein (p.Gln853Arg).
Color Diagnostics, LLC DBA Color Health	RCV000130947	SCV001348069	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 853 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130947	SCV003848409	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).
GeneDx	RCV004772843	SCV005385195	uncertain significance	not provided	2024-01-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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 2786A>G