Submissions for variant NM_000059.4(BRCA2):c.2798C>G (p.Thr933Arg)

dbSNP: rs276174830

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001191192	SCV001358930	uncertain significance	Hereditary cancer-predisposing syndrome	2019-07-03	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with arginine at codon 933 of the BRCA2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact 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 not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001314174	SCV001504698	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-08-12	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51346). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with arginine at codon 933 of the BRCA2 protein (p.Thr933Arg). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and arginine.
Ambry Genetics	RCV001191192	SCV002748334	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-02	criteria provided, single submitter	clinical testing	The p.T933R variant (also known as c.2798C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 2798. The threonine at codon 933 is replaced by arginine, an amino acid with similar properties. This variant was reported in 2/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001191192	SCV003850144	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).
Sharing Clinical Reports Project (SCRP)	RCV000077286	SCV000109083	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2008-04-07	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077286	SCV000146110	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-10-19	no assertion criteria provided	clinical testing