ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2888C>T (p.Thr963Ile) (rs730881443)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159847 SCV000209890 uncertain significance not provided 2017-08-11 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2888C>T at the cDNA level, p.Thr963Ile (T963I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). Using alternate nomenclature, this variant would be defined as BRCA1 3007C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Thr963Ile was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Thr963Ile occurs at a position that is not conserved and is located in the DNA binding domain and the RAD51 binding domain (Chen 1998, Narod 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Thr963Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000213875 SCV000278318 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-11 criteria provided, single submitter clinical testing
Invitae RCV000637682 SCV000759152 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-02 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 963 of the BRCA1 protein (p.Thr963Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. 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: 182077). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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