ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5200G>A (p.Glu1734Lys) (rs786202543)

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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 RCV000165399 SCV000216126 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000165399 SCV000903154 likely benign Hereditary cancer-predisposing syndrome 2016-09-09 criteria provided, single submitter clinical testing
GeneDx RCV000485722 SCV000572788 uncertain significance not provided 2018-08-22 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5200G>A at the cDNA level, p.Glu1734Lys (E1734K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant, also defined as BRCA2 5428G>A using alternate nomenclature, has been reported in at least one family with breast and/or ovarian cancer (Konstantopoulou 2014). BRCA2 Glu1734Lys was not observed at a significant allele frequency 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 a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Glu1734Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000205413 SCV000260139 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-29 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1734 of the BRCA2 protein (p.Glu1734Lys). 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 reported individuals affected with hereditary breast and/or ovarian cancer (PMID: 24010542, 29470806). ClinVar contains an entry for this variant (Variation ID: 185896). 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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