Submissions for variant NM_000059.4(BRCA2):c.5923T>C (p.Cys1975Arg)

dbSNP: rs1555284462

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000568115	SCV000661358	uncertain significance	Hereditary cancer-predisposing syndrome	2016-09-16	criteria provided, single submitter	clinical testing	The p.C1975R variant (also known as c.5923T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 5923. The cysteine at codon 1975 is replaced by arginine, an amino acid with highly dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0003% (greater than 300000 alleles tested) in our clinical cohort. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001858083	SCV002223248	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-04-16	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with arginine at codon 1975 of the BRCA2 protein (p.Cys1975Arg). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 479350). 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. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000568115	SCV003850784	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).