ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5503A>G (p.Asn1835Asp) (rs80358771)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044672 SCV000072685 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 1835 of the BRCA2 protein (p.Asn1835Asp). The aspragine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs80358771, ExAC 0.01%). This variant has been reported in an individual affected with breast/ovarian cancer (PMID: 21120943). ClinVar contains an entry for this variant (Variation ID: 51873). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; 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. 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.
Ambry Genetics RCV000213098 SCV000276446 likely benign Hereditary cancer-predisposing syndrome 2015-06-26 criteria provided, single submitter clinical testing
GeneDx RCV000220592 SCV000279751 uncertain significance not provided 2019-01-14 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5503A>G at the cDNA level, p.Asn1835Asp (N1835D) 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 5731A>G. This variant was observed in 1/1,153 patients undergoing BRCA1/2 testing for a personal and/or family history of breast and/or ovarian cancer (Caux-Moncoutier 2011). BRCA2 Asn1835Asp was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Asn1835Asp occurs at a position that is not conserved and is located in the RAD51 binding domain (Roy 2012). 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 Asn1835Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000213098 SCV000903957 likely benign Hereditary cancer-predisposing syndrome 2017-02-09 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113440 SCV000146626 uncertain significance Breast-ovarian cancer, familial 2 2004-11-25 no assertion criteria provided clinical testing

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