ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5501C>T (p.Thr1834Ile) (rs730881500)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160012 SCV000210226 uncertain significance not provided 2019-01-02 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5501C>T at the cDNA level, p.Thr1834Ile (T1834I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). Using alternate nomenclature, this variant would be defined as BRCA1 5620C>T. This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. BRCA1 Thr1834Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRCT2 domain and a region known to interact with multiple proteins (Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Thr1834Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000218401 SCV000275019 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000467034 SCV000549305 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-10-31 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1834 of the BRCA1 protein (p.Thr1834Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs730881500, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 182171). 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: "Deleterious"; PolyPhen-2: "Probably 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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