ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6109G>A (p.Glu2037Lys) (rs1064795651)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483807 SCV000571654 uncertain significance not provided 2016-09-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6109G>A at the cDNA level, p.Glu2037Lys (E2037K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). Using alternate nomenclature, this variant would be defined as BRCA2 6337G>A. This variant was observed in at least one individual with a personal history of a Lynch syndrome associated cancer and/or polyps, undergoing genetic testing using a multigene panel (Yurgelun 2015). BRCA2 Glu2037Lys 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 Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu2037Lys occurs at a position that is not conserved and is not located in a known functional domain (Cole 2011). 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 Glu2037Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000811660 SCV000951938 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2037 of the BRCA2 protein (p.Glu2037Lys). 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 been observed in an individual undergoing testing for Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 422241). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; 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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