Submissions for variant NM_000059.4(BRCA2):c.2446G>A (p.Glu816Lys)

dbSNP: rs730881514

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160048	SCV000210290	uncertain significance	not provided	2014-05-15	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.2446G>A at the cDNA level, p.Glu816Lys (E816K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu816Lys 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 Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu816Lys occurs at a position that is moderately conserved across species and is located in the region that interacts with Nucleophosmin 1 (UniProt). In addition, 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 Glu816Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637641	SCV000759108	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-04-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 816 of the BRCA2 protein (p.Glu816Lys). 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: 182189). 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.
Ambry Genetics	RCV001015572	SCV001176419	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-08	criteria provided, single submitter	clinical testing	The p.E816K variant (also known as c.2446G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 2446. The glutamic acid at codon 816 is replaced by lysine, an amino acid with similar properties. 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.
Color Diagnostics, LLC DBA Color Health	RCV001015572	SCV001348067	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 816 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not 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). The 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001015572	SCV003848323	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237595	SCV005885527	uncertain significance	not specified	2025-02-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2446G>A (p.Glu816Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 243424 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2446G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 182189). Based on the evidence outlined above, the variant was classified as uncertain significance.