ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6823G>A (p.Glu2275Lys) (rs587782362)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131323 SCV000186296 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000131323 SCV000903886 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-17 criteria provided, single submitter clinical testing
GeneDx RCV000160121 SCV000210405 uncertain significance not provided 2014-04-23 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6823G>A at the cDNA level, p.Glu2275Lys (E2275K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu2275Lys 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. This variant is a non-conservative substitution in which a negative polar amino acid is replaced with a positive polar one, altering a position that is highly variable throughout evolution and is not located in a known functional domain. In silico analyses predict this variant to have a benign effect on protein structure and function. Based on the currently available information, we consider BRCA2 Glu2275Lys to be a variant of uncertain significance.
Invitae RCV000812168 SCV000952472 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2275 of the BRCA2 protein (p.Glu2275Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 142290). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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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