ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6698C>A (p.Ala2233Asp) (rs41293501)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165875 SCV000216625 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Breast Cancer Information Core (BIC) (BRCA2) RCV000113630 SCV000146912 uncertain significance Breast-ovarian cancer, familial 2 2002-06-20 no assertion criteria provided clinical testing
Color RCV000165875 SCV000683797 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-08 criteria provided, single submitter clinical testing
Counsyl RCV000113630 SCV000784808 uncertain significance Breast-ovarian cancer, familial 2 2016-12-14 criteria provided, single submitter clinical testing
GeneDx RCV000212250 SCV000210400 uncertain significance not provided 2018-02-26 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6698C>A at the cDNA level, p.Ala2233Asp (A2233D) at the protein level, and results in the change of an Alanine to an Aspartic Acid (GCT>GAT). Using alternate nomenclature, this variant would be defined as BRCA2 6926C>A. This variant was observed in at least two individuals with triple negative breast cancer and at least one other from a hereditary diffuse gastric cancer family (Couch 2015, Wong-Brown 2015, Hansford 2015). BRCA2 Ala2233Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ala2233Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000165875 SCV000747803 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-16 criteria provided, single submitter clinical testing
Invitae RCV000045020 SCV000073033 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 2233 of the BRCA2 protein (p.Ala2233Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is present in population databases (rs41293501, ExAC 0.002%). This variant has been observed in individuals affected with breast cancer (PMID: 25682074, 25452441). Additionally, this variant has been observed in an individual affected with hereditary diffuse gastric cancer (PMID: 26182300). ClinVar contains an entry for this variant (Variation ID: 52159). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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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