Submissions for variant NM_000059.4(BRCA2):c.5624A>G (p.Lys1875Arg)

dbSNP: rs587782583

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131917	SCV000186972	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-20	criteria provided, single submitter	clinical testing	The p.K1875R variant (also known as c.5624A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5624. The lysine at codon 1875 is replaced by arginine, an amino acid with highly similar 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.
GeneDx	RCV000223072	SCV000279789	uncertain significance	not provided	2016-01-11	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.5624A>G at the cDNA level, p.Lys1875Arg (K1875R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). Using alternate nomenclature, this variant would be defined as BRCA2 5852A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Lys1875Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Lys1875Arg occurs at a position that is not conserved and is not located in a known functional domain (Borg 2010). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Lys1875Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688314	SCV000815920	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1875 of the BRCA2 protein (p.Lys1875Arg). 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: 142607). 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	RCV000131917	SCV003848961	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).