ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7354A>G (p.Asn2452Asp) (rs398122580)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213983 SCV000276426 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-16 criteria provided, single submitter clinical testing The p.N2452D variant (also known as c.7354A>G), located in coding exon 13 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7354. The asparagine at codon 2452 is replaced by aspartic acid, an amino acid with highly similar properties. Functional studies showed that cell lines transfected with the p.N2452D variant showed survival rates and apoptosis rates statistically similar to the wild type cell line after being dosed with DNA cross link-inducing drug cisplatin (CDDP) (Warren CR et al. Exp Cell Res. 2011 Sep; 317(15):2099-109). This variant has also been reported as a variant of unknown significance in one individual diagnosed with breast cancer (D'Argenio V et al. Clin Chim Acta. 2015 Jun; 446:221-5). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000417844 SCV000520977 likely benign not specified 2017-11-09 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587585 SCV000695057 uncertain significance not provided 2016-10-24 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7354A>G (p.Asn2452Asp) variant located in the BRCA2 linker region (Warren_2011) causes a missense change with 3/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a benign outcome for this variant. The variant of interest has not been observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in an affected individual via a publication. A functional study indicates the variant could alter wild type function, however, the implications of these findings is not well established for tumorigenesis. Multiple clinical diagnostic laboratories/databases cite the variant as "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as "Variant of Uncertain Significance (VUS)."
Invitae RCV000685760 SCV000813257 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-24 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 2452 of the BRCA2 protein (p.Asn2452Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer and/or a family history of breast cancer (PMID: 21741379). ClinVar contains an entry for this variant (Variation ID: 91475). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Experimental studies have not detected an impact for this missense variant on BRCA2 function (PMID: 21741379). 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.
Color Health, Inc RCV000213983 SCV000911818 likely benign Hereditary cancer-predisposing syndrome 2016-06-21 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000076992 SCV000108789 uncertain significance Breast-ovarian cancer, familial 2 2009-12-15 no assertion criteria provided clinical testing

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