ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7739A>G (p.Gln2580Arg) (rs1064795508)

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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 RCV000573542 SCV000668749 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000573542 SCV000910439 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing
GeneDx RCV000480812 SCV000571384 uncertain significance not provided 2018-06-08 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7739A>G at the cDNA level, p.Gln2580Arg (Q2580R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). Using alternate nomenclature, this variant would be defined as BRCA2 7967A>G. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Gln2580Arg was not observed in large population cohorts (Lek 2016). Since BRCA2 Gln2580Arg is located within the DNA binding domain (Yang 2002). 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 Gln2580Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000637758 SCV000759235 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-10-27 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 2580 of the BRCA2 protein (p.Gln2580Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine 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: 422026). 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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