ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5900A>G (p.Lys1967Arg) (rs959089047)

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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 RCV000563594 SCV000668673 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Color RCV000563594 SCV000683740 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-12 criteria provided, single submitter clinical testing
GeneDx RCV000487031 SCV000564788 uncertain significance not provided 2018-08-24 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5900A>G at the cDNA level, p.Lys1967Arg (K1967R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). Using alternate nomenclature, this variant would be defined as BRCA2 6128A>G. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Lys1967Arg was not observed in large population cohorts (Lek 2016). This variant is located in the RAD51 Binding Domain (Roy 2012). While protein-based in silico analysis supports that this variant does not alter protein structure/function, splicing models predict the creation of a new splice site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA2 Lys1967Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000553708 SCV000635479 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-04-30 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 1967 of the BRCA2 protein (p.Lys1967Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. 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: 418085). 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 arginine 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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