ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5492T>C (p.Ile1831Thr) (rs587782007)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130427 SCV000185291 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Counsyl RCV000409845 SCV000488496 uncertain significance Breast-ovarian cancer, familial 2 2016-04-13 criteria provided, single submitter clinical testing
GeneDx RCV000766626 SCV000210356 uncertain significance not provided 2016-02-24 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5492T>C at the cDNA level, p.Ile1831Thr (I1831T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). Of note, this variant is also known as BRCA2 5720T>C using alternate nomenclature. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ile1831Thr 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 Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ile1831Thr 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 information, it is unclear whether BRCA2 Ile1831Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000459937 SCV000549515 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1831 of the BRCA2 protein (p.Ile1831Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs587782007, ExAC 0.002%). This variant has been reported in individuals from families with a predisposition to breast cancer and/or ovarian cancer (PMID: 27062684). ClinVar contains an entry for this variant (Variation ID: 141782). 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 threonine 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160091 SCV000600642 uncertain significance not specified 2016-11-22 criteria provided, single submitter clinical testing

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