ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2446G>A (p.Glu816Lys) (rs730881514)

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Total submissions: 2
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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.
Invitae RCV000637641 SCV000759108 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-10-13 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 816 of the BRCA2 protein (p.Glu816Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 182189). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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