ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4181C>T (p.Thr1394Ile) (rs397507226)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164912 SCV000215600 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000164912 SCV000909275 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
GeneDx RCV000236566 SCV000294090 uncertain significance not provided 2016-11-02 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4181C>T at the cDNA level, p.Thr1394Ile (T1394I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). Using alternate nomenclature, this variant has been previously published as BRCA1 4300C>T. This variant was observed in at least one individual with breast cancer (Pal 2015) and on functional interrogation did not cause a decrease in transcriptional activation (Woods 2016). BRCA1 Thr1394Ile 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 Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Thr1394Ile occurs at a position that is conserved across species and is located in the SCD domain and a region known to interact with multiple proteins (Narod 2004, Paul 2014). 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 Thr1394Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000530171 SCV000635952 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1394 of the BRCA1 protein (p.Thr1394Ile). The threonine residue is highly 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 been reported in an individual affected with breast cancer (PMID: 26287763). this variant is also known as 4300C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 37573). 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: "Benign"; Align-GVGD: "Class C65"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP) RCV000031154 SCV000053754 likely benign Breast-ovarian cancer, familial 1 2012-08-06 no assertion criteria provided clinical testing

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