Submissions for variant NM_000059.4(BRCA2):c.1760C>G (p.Thr587Arg)

dbSNP: rs786203316

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166573	SCV000217375	uncertain significance	Hereditary cancer-predisposing syndrome	2014-10-22	criteria provided, single submitter	clinical testing	The p.T587R variant (also known as c.1760C>G and 1988C>G) is located in coding exon 9 of the BRCA2 gene. This alteration results from a C to G substitution at nucleotide position 1760. The threonine at codon 587 is replaced by arginine, an amino acid with some similar 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. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 64,000 alleles tested) in our clinical cohort. 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 p.T587R remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000553477	SCV000635174	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 587 of the BRCA2 protein (p.Thr587Arg). 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: 186910). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000166573	SCV003851616	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).