ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2924T>A (p.Ile975Asn) (rs398122756)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000624980 SCV000744433 likely benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000624980 SCV000743278 likely benign Breast-ovarian cancer, familial 2 2017-07-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588340 SCV000694648 uncertain significance not provided 2016-11-21 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.2924T>A (p.Ile975Asn) variant causes a missense change involving a non-conserved nucleotide, which 3/5 in silico tools predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest has not been observed in controls (ExAC, 1000 Gs, or ESP), nor has it been, to our knowledge, reported in affected individuals via publications. A database cites the variant with a classification of "UV." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000466456 SCV000549829 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-07 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with asparagine at codon 975 of the BRCA2 protein (p.Ile975Asn). The isoleucine residue is weakly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. This variant has been reported in individuals affected with breast cancer in the Leiden Open-source Variation Database (PMID: 21520333) 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 asparagine 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, this variant is a rare missense change that is not predicted to affect protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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