ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1822G>A (p.Asp608Asn) (rs1064794170)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563223 SCV000666151 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
GeneDx RCV000758867 SCV000568061 uncertain significance not provided 2016-06-02 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1822G>A at the cDNA level, p.Asp608Asn (D608N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAC>AAC). Using alternate nomenclature, this variant would be defined as BRCA2 2050G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asp608Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Asp608Asn occurs at a position that is not conserved and is not located in a known functional domain. 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 Asp608Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000637768 SCV000759245 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-10 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 608 of the BRCA2 protein (p.Asp608Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. 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: 419884). 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 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 RCV000758867 SCV000887763 uncertain significance not provided 2017-10-18 criteria provided, single submitter clinical testing

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