ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1666A>G (p.Asn556Asp) (rs587781794)

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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 RCV000130055 SCV000184882 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000130055 SCV000903458 likely benign Hereditary cancer-predisposing syndrome 2017-05-01 criteria provided, single submitter clinical testing
GeneDx RCV000587388 SCV000279802 uncertain significance not provided 2018-05-02 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1666A>G at the cDNA level, p.Asn556Asp (N556D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). Using alternate nomenclature, this variant would be defined as BRCA2 1894A>G. This variant has been reported in at least one individual undergoing BRCA1/2 testing (Houdayer 2012). BRCA2 Asn556Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Asn556Asp is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Asn556Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587388 SCV000694556 uncertain significance not provided 2016-08-29 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.1666A>G (p.Asn556Asp) variant involves the alteration of a non-conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome for this variant. The variant affects a non-conserved amino acid and is not located in a known functional domain. 3/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts no effect on ESE binding, which is further supported by a functional study (Houdayer_2012). The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP), nor has it been reported in affected individuals via publications. However, a reputable database cites the variant to co-occur with another pathogenic BRCA2 variant, c.4093delT (p.Cys1365ValfsX9). Multiple clinical laboratories have cited the variant as "uncertain significance." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a VUS-possible benign until additional information becomes available.
Invitae RCV000543145 SCV000635173 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-03 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 556 of the BRCA2 protein (p.Asn556Asp). 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 not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 141498). 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 aspartic acid 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 RCV000587388 SCV000888990 uncertain significance not provided 2018-04-23 criteria provided, single submitter clinical testing

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