Submissions for variant NM_000059.4(BRCA2):c.5518G>C (p.Gly1840Arg)

dbSNP: rs398122533

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464863	SCV000549708	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1840 of the BRCA2 protein (p.Gly1840Arg). This variant is not present in population databases (gnomAD no frequency). 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: 91416). 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.
GeneDx	RCV000478840	SCV000567396	uncertain significance	not provided	2019-09-18	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; Also known as 5746G>C
Ambry Genetics	RCV000510044	SCV000608237	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-11	criteria provided, single submitter	clinical testing	The p.G1840R variant (also known as c.5518G>C), located in coding exon 10 of the BRCA2 gene, results from a G to C substitution at nucleotide position 5518. The glycine at codon 1840 is replaced by arginine, 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.
Color Diagnostics, LLC DBA Color Health	RCV000510044	SCV000688930	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 1840 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 BRCA2-related disorders 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	RCV000510044	SCV003848882	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	RCV000076933	SCV004846588	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 1840 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 BRCA2-related disorders 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.
Sharing Clinical Reports Project (SCRP)	RCV000076933	SCV000108730	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2009-12-07	no assertion criteria provided	clinical testing