ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7456A>G (p.Asn2486Asp) (rs730881556)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160133 SCV000210424 uncertain significance not provided 2014-10-01 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7456A>G at the cDNA level, p.Asn2486Asp (N2486D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn2486Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Asn2486Asp occurs at a position that is moderately conserved through mammals and is located in the region of interaction with FANCD2 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Asn2486Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000476586 SCV000549514 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-06-06 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 2486 of the BRCA2 protein (p.Asn2486Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine 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 a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 182240). 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, this variant has uncertain impact on BRCA2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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