ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.788G>A (p.Gly263Asp) (rs397509319)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159945 SCV000210088 uncertain significance not provided 2014-02-10 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.788G>A at the cDNA level, p.Gly263Asp (G263D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Gly263Asp 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 substitution in which a neutral non-polar amino acid is replaced with a negative polar one, altering a position that is moderately conserved throughout evolution and is not located in a known functional domain. In silico analyses predict this variant to have a benign effect on protein structure and function. Based on the currently available information, we consider BRCA1 Gly263Asp to be a variant of uncertain significance.
Ambry Genetics RCV000165328 SCV000216051 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000409328 SCV000488381 uncertain significance Breast-ovarian cancer, familial 1 2016-03-11 criteria provided, single submitter clinical testing
Invitae RCV000559360 SCV000636077 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 263 of the BRCA1 protein (p.Gly263Asp). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 182127). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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