ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1448T>C (p.Ile483Thr) (rs80357489)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047479 SCV000075492 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-09-04 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 483 of the BRCA1 protein (p.Ile483Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 54255). 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 threonine 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. 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.
GeneDx RCV000478226 SCV000566062 uncertain significance not provided 2017-12-04 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1448T>C at the cDNA level, p.Ile483Thr (I483T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). Using alternate nomenclature, this variant would be defined as BRCA1 1567T>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ile483Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ile483Thr is located within the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Ile483Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000575874 SCV000665343 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-20 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000575874 SCV000909586 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-02 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083170 SCV000115244 uncertain significance Breast-ovarian cancer, familial 1 2008-03-19 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083170 SCV000144098 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing

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