ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5296A>G (p.Ile1766Val) (rs886039314)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255771 SCV000321442 uncertain significance not provided 2016-06-27 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5296A>G at the cDNA level, p.Ile1766Val (I1766V) at the protein level, and results in the change of an Isoleucine to a Valine (ATC>GTC). Using alternate nomenclature, this variant would be defined as BRCA1 5415A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ile1766Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Ile1766Val occurs at a position that is not conserved and is located in the BRCT 2 domain and in a region known to interact with multiple other proteins (Paul 2014, Uniprot). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Ile1766Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000771387 SCV000903726 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-30 criteria provided, single submitter clinical testing
Invitae RCV000813828 SCV000954207 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-04 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1766 of the BRCA1 protein (p.Ile1766Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 265052). 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 valine 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. This variant disrupts the p.Ile1766 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 20737206, 17308087), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.

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