ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8527A>G (p.Asn2843Asp) (rs876660403)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219865 SCV000277802 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-17 criteria provided, single submitter clinical testing
GeneDx RCV000483025 SCV000571196 uncertain significance not provided 2017-02-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8527A>G at the cDNA level, p.Asn2843Asp (N2843D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). Using alternate nomenclature, this variant would be defined as BRCA2 8755A>G. This variant has been observed in at least one individual with breast cancer (Carney 2010). BRCA2 Asn2843Asp 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 Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Asn2843Asp occurs at a position that is not conserved and is located in the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Asn2843Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GenomeConnect, ClinGen RCV000483025 SCV000986772 not provided not provided no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 04/25/2018 by GTR ID Credit Valley Hospital Department of Laboratory Medicine. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000541298 SCV000635669 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 2843 of the BRCA2 protein (p.Asn2843Asp). The asparagine residue is highly 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 been reported in the literature in an individual affected with breast cancer (PMID: 21218378). ClinVar contains an entry for this variant (Variation ID: 233431). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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