ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3071T>A (p.Ile1024Asn) (rs764921920)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481872 SCV000569707 uncertain significance not provided 2018-05-02 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3071T>A at the cDNA level, p.Ile1024Asn (I1024N) at the protein level, and results in the change of an Isoleucine to an Asparagine (ATT>AAT). Using alternate nomenclature, this variant would be defined as BRCA2 3299T>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ile1024Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in BRC1 domain and the RAD51 binding domain (Cole 2011, Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Ile1024Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000545081 SCV000635264 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-04-01 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with asparagine at codon 1024 of the BRCA2 protein (p.Ile1024Asn). The isoleucine residue is weakly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is present in population databases (rs764921920, ExAC 0.003%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 420747). 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 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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