ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5365A>G (p.Lys1789Glu) (rs587782240)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130942 SCV000185855 likely benign Hereditary cancer-predisposing syndrome 2017-03-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (benign),Other strong data supporting benign classification
Integrated Genetics/Laboratory Corporation of America RCV000781107 SCV000918943 uncertain significance not specified 2018-08-20 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5365A>G (p.Lys1789Glu) results in a conservative amino acid change located in the BRCA2 repeat region (IPR002093) of 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 245846 control chromosomes (gnomAD). 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.5365A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000198002 SCV000254192 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-04-27 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 1789 of the BRCA2 protein (p.Lys1789Glu). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamic acid. 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: 142108). 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 glutamic acid 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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