ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7826G>T (p.Gly2609Val) (rs80359009)

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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 RCV000216317 SCV000276696 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Well-characterized mutation at same position,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence,Deficient protein function in appropriate functional assay(s)
GeneDx RCV000255714 SCV000321485 uncertain significance not provided 2018-06-07 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7826G>T at the cDNA level, p.Gly2609Val (G2609V) at the protein level, and results in the change of a Glycine to a Valine (GGT>GTT). Using alternate nomenclature, this variant would be defined as BRCA2 8054G>T. Functional assays interrogating homology directed repair demonstrated a pathogenic effect (Guidugli 2018). BRCA2 Gly2609Val was not observed in large population cohorts (Lek 2016). This variant is located in 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 Gly2609Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000556406 SCV000635613 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-03-22 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 2609 of the BRCA2 protein (p.Gly2609Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 232537). 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. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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