ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2491T>G (p.Tyr831Asp) (rs1060502350)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464267 SCV000549381 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-08-24 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with aspartic acid at codon 831 of the BRCA1 protein (p.Tyr831Asp). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine 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. 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 also 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 novel 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.
GeneDx RCV000481004 SCV000564726 uncertain significance not provided 2014-10-28 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2491T>G at the cDNA level, p.Tyr831Asp (Y831D) at the protein level, and results in the change of a Tyrosine to an Aspartic Acid (TAT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Tyr831Asp 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 Tyrosine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Tyr831Asp occurs at a position that is poorly conserved across species and is located in DNA-binding domain (Narod 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Tyr831Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.

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