ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6233G>T (p.Gly2078Val) (rs769883812)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484329 SCV000570117 uncertain significance not provided 2016-04-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6233G>T at the cDNA level, p.Gly2078Val (G2078V) at the protein level, and results in the change of a Glycine to a Valine (GGA>GTA). Using alternate nomenclature, this variant would be defined as BRCA2 6461G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gly2078Val 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 Glycine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Gly2078Val occurs at a position that is conserved in mammals and is located within the BRC8 domain and the RAD51 binding domain (Cole 2011, Roy 2012). In silico analyses predict that this variant is probably damaging to protein structure and function, and multiple splicing models predict that this variant may create a cryptic splice donor site for exon 11 and lead to abnormal splicing. 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 Gly2078Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000821918 SCV000962692 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-06 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 2078 of the BRCA2 protein (p.Gly2078Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs769883812, ExAC 0.002%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 421039). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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