ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4336A>G (p.Ile1446Val) (rs876661017)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000573581 SCV000661382 likely benign Hereditary cancer-predisposing syndrome 2016-11-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
GeneDx RCV000222291 SCV000279202 uncertain significance not provided 2016-02-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4336A>G at the cDNA level, p.Ile1446Val (I1446V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). Using alternate nomenclature, this variant would be defined as BRCA2 4564A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ile1446Val 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 Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ile1446Val occurs at a position that is not conserved and is located in the BRC3 domain and the POLH binding domain (Cole 2011, Buisson 2014). 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 Ile1446Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000800936 SCV000940681 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-05 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1446 of the BRCA2 protein (p.Ile1446Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 234426). 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 valine 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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