ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6894A>T (p.Glu2298Asp) (rs876661199)

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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 RCV000565312 SCV000661435 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000220725 SCV000279771 uncertain significance not provided 2016-01-06 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6894A>T at the cDNA level, p.Glu2298Asp (E2298D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAT). Using alternate nomenclature, this variant would be defined as BRCA2 7122A>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu2298Asp 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 Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. BRCA2 Glu2298Asp occurs at a position that is not conserved and is not located in a known functional domain (Borg 2010, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Glu2298Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000686463 SCV000813982 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-09 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 2298 of the BRCA2 protein (p.Glu2298Asp). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. 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: 234753). 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: "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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