ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8633A>G (p.Glu2878Gly) (rs786203358)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166633 SCV000217437 uncertain significance Hereditary cancer-predisposing syndrome 2014-10-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000223363 SCV000279955 uncertain significance not provided 2016-03-03 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8633A>G at the cDNA level, p.Glu2878Gly (E2878G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAA>GGA). Using alternate nomenclature, this variant would be defined as BRCA2 8861A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu2878Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu2878Gly occurs at a position that is not conserved 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 evidence, it is unclear whether BRCA2 Glu2878Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000637779 SCV000759258 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-11-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 2878 of the BRCA2 protein (p.Glu2878Gly). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and glycine. 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: 186963). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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