ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2233A>G (p.Lys745Glu) (rs374691587)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130703 SCV000185590 likely benign Hereditary cancer-predisposing syndrome 2017-10-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign),Other strong data supporting benign classification
GeneDx RCV000160045 SCV000210285 likely benign not specified 2017-11-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000197517 SCV000254172 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 745 of the BRCA2 protein (p.Lys745Glu). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs374691587, ExAC 0.01%). This variant has been reported in individuals affected with breast cancer (PMID: 22034289, 20051372). ClinVar contains an entry for this variant (Variation ID: 141961). 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 also 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. 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.
Counsyl RCV000410547 SCV000488508 uncertain significance Breast-ovarian cancer, familial 2 2016-04-15 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000160045 SCV000591795 uncertain significance not specified 2012-11-15 criteria provided, single submitter clinical testing
Mendelics RCV000197517 SCV000838768 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000130703 SCV000905803 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000160045 SCV000916973 uncertain significance not specified 2017-12-26 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.2233A>G (p.Lys745Glu) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 7/277046 control chromosomes at a frequency of 0.0000253, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). It has been reported in multiple affected individuals without strong evidence for causality. In addition, three clinical diagnostic laboratories classified this variant as VUS and two other labs classified it as likely benign via ClinVar, all without evidence for independent evaluation. Taken together, this variant is classified as VUS.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985472 SCV001133703 uncertain significance not provided 2019-02-15 criteria provided, single submitter clinical testing
Mendelics RCV000410547 SCV001139025 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing

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