Submissions for variant NM_000059.4(BRCA2):c.2026T>C (p.Cys676Arg)

gnomAD frequency: 0.00001  dbSNP: rs397507280

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000031353	SCV000296529	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816423	SCV000956931	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 676 of the BRCA2 protein (p.Cys676Arg). This variant is present in population databases (rs397507280, gnomAD 0.002%). 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: 37772). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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	RCV001014109	SCV001174783	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-01	criteria provided, single submitter	clinical testing	The p.C676R variant (also known as c.2026T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 2026. The cysteine at codon 676 is replaced by arginine, an amino acid with highly dissimilar properties. This amino acid position is poorly 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.
Color Diagnostics, LLC DBA Color Health	RCV001014109	SCV001339999	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with arginine at codon 676 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 been identified in 2/249190 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001509436	SCV001716145	uncertain significance	not provided	2020-03-02	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV001014109	SCV003846448	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	RCV001509436	SCV004031818	uncertain significance	not provided	2023-08-31	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 2254T>C; This variant is associated with the following publications: (PMID: 22874498)
All of Us Research Program, National Institutes of Health	RCV000031353	SCV004846999	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with arginine at codon 676 of the BRCA2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, 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 2/249190 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005357195	SCV005915476	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2	2021-03-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031353	SCV000053958	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-08-31	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV001509436	SCV002029152	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 03-10-2020 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.