ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4531G>A (p.Glu1511Lys) (rs376338226)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130226 SCV000185066 likely benign Hereditary cancer-predisposing syndrome 2016-12-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
GeneDx RCV000589639 SCV000210337 uncertain significance not provided 2018-09-05 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4531G>A at the cDNA level, p.Glu1511Lys (E1511K) 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 4759G>A. This variant was observed in at least one individual with neuroblastoma (Lasorsa 2016). BRCA2 Glu1511Lys was observed at an allele frequency of 0.02% (6/30,738) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Glu1511Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000411643 SCV000488154 uncertain significance Breast-ovarian cancer, familial 2 2016-01-07 criteria provided, single submitter clinical testing
Invitae RCV000476816 SCV000549718 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1511 of the BRCA2 protein (p.Glu1511Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs376338226, ExAC 0.01%) but has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 141630). 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. 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.
Integrated Genetics/Laboratory Corporation of America RCV000589639 SCV000694778 uncertain significance not provided 2016-06-27 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4531G>A (p.Glu1511Lys) variant involves the alteration of a non-conserved nucleotide. The variant lies in RAD-binding domain however it is unknown whether it affects critical residues. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 4/120194 control chromosomes at a frequency of 0.0000333, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). Two clinical diagnostic laboratories have classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of sufficient clinical information and the lack of functional studies, the variant is currently classified as a variant of uncertain significance (VUS) until additional information becomes available.
PreventionGenetics,PreventionGenetics RCV000589639 SCV000805707 uncertain significance not provided 2017-12-06 criteria provided, single submitter clinical testing
Color RCV000130226 SCV000903770 likely benign Hereditary cancer-predisposing syndrome 2015-07-21 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000476816 SCV000586950 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-04-14 no assertion criteria provided clinical testing

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