ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3098A>T (p.Asp1033Val) (rs141702094)

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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 RCV000570313 SCV000665385 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000236981 SCV000293564 uncertain significance not provided 2015-11-19 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3098A>T at the cDNA level, p.Asp1033Val (D1033V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). Using alternate nomenclature, this variant would be defined as BRCA2 3326A>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asp1033Val was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Aspartic Acid and Valine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Asp1033Val occurs at a position that is conserved across species and is located within a BRC repeat motif (Roy 2012, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Asp1033Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000474695 SCV000549653 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 1033 of the BRCA2 protein (p.Asp1033Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs141702094, ExAC 0.02%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 246140). 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"). 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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