ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.902A>G (p.Asp301Gly) (rs730881508)

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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 RCV000166054 SCV000216815 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Color RCV000166054 SCV000689170 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-26 criteria provided, single submitter clinical testing
GeneDx RCV000160032 SCV000210259 uncertain significance not provided 2014-01-07 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.902A>G at the cDNA level and p.Asp301Gly (D301G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This variant is a non-conservative amino acid substitution in which a negative polar residue is replaced with a neutral non-polar one, altering a position that is only moderately conserved throughout evolution, and is not in a known functional domain. In silico analyses predict this variant to have a benign effect on protein structure and function. Based on currently available information, we consider this to be a variant of uncertain significance.
Invitae RCV000545109 SCV000635711 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 301 of the BRCA2 protein (p.Asp301Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs730881508, ExAC 0.003%). This variant has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 182182). 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 glycine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant has uncertain impact on BRCA2 function. 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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