Submissions for variant NM_000059.4(BRCA2):c.5329A>G (p.Lys1777Glu)

dbSNP: rs730881537

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160086	SCV000210350	uncertain significance	not provided	2014-07-26	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA2 c.5329A>G at the cDNA level, p.Lys1777Glu (K1777E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Lys1777Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Lys1777Glu occurs at a position that is moderately conserved across species and is located in the region responsible for interacting with POLH. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Lys1777Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001309197	SCV001498687	uncertain significance	Hereditary breast ovarian cancer syndrome	2020-10-08	criteria provided, single submitter	clinical testing	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. 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. This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 182216). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with glutamic acid at codon 1777 of the BRCA2 protein (p.Lys1777Glu). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamic acid.
University of Washington Department of Laboratory Medicine, University of Washington	RCV003157432	SCV003847167	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).