ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7786G>A (p.Gly2596Arg) (rs398122591)

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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 RCV000509715 SCV000608032 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770731 SCV000902212 uncertain significance Breast and/or ovarian cancer 2017-05-12 criteria provided, single submitter clinical testing
Color RCV000509715 SCV000683904 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing
Counsyl RCV000077009 SCV000489011 uncertain significance Breast-ovarian cancer, familial 2 2016-08-02 criteria provided, single submitter clinical testing
GeneDx RCV000160142 SCV000210447 uncertain significance not provided 2017-03-10 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7786G>A at the cDNA level, p.Gly2596Arg (G2596R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant, also known as 8014G>A using alternate nomenclature, has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gly2596Arg was not observed at a significant frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Gly2596Arg occurs at a position that is conserved across species and is located within the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Gly2596Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000197789 SCV000254212 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 2596 of the BRCA2 protein (p.Gly2596Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs398122591, ExAC 0.001%). This variant has been reported in the Leiden Open-source Variation Database, in an individual affected with breast cancer (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 91492). 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 disruptive, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077009 SCV000296520 uncertain significance Breast-ovarian cancer, familial 2 2016-05-07 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077009 SCV000108806 uncertain significance Breast-ovarian cancer, familial 2 2010-03-23 no assertion criteria provided clinical testing

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