ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4649C>T (p.Thr1550Ile) (rs80357076)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195394 SCV000076631 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1550 of the BRCA1 protein (p.Thr1550Ile). The threonine residue is weakly 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 acute lymphoblastic leukemia (ALL), and is also known as T1571I in the literature (PMID: 26580448). This variant has been reported in affected patients in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 55251). This variant has been reported not to substantially affect BRCA1 protein function (PMID: 28781887). 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.
Ambry Genetics RCV000129109 SCV000183820 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-24 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000048618 SCV000210182 uncertain significance not provided 2018-04-24 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4649C>T at the cDNA level, p.Thr1550Ile (T1550I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant is also defined as BRCA1 4768C>T using alternate nomenclature, and BRCA1 T1571I using an alternate transcript. This variant has been observed in at least one individual with hyperdiploid acute lymphoblastic leukemia (Zhang 2015). Functional interrogation of this variant by in vitro transcription activation assay demonstrated activity exceeding wild type (Woods 2016). BRCA1 Thr1550Ile was not observed in large population cohorts (Lek 2016). This variant is located in a region known to interact with multiple proteins (Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Thr1550Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048618 SCV000296308 uncertain significance not provided 2018-10-05 criteria provided, single submitter clinical testing
Counsyl RCV000112373 SCV000488717 uncertain significance Breast-ovarian cancer, familial 1 2016-06-01 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000129109 SCV000679698 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Color RCV000129109 SCV000688507 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-03 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000112373 SCV001428451 uncertain significance Breast-ovarian cancer, familial 1 2019-04-08 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112373 SCV000145139 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV001248951 SCV001422731 uncertain significance not specified 2020-01-22 no assertion criteria provided curation The p.Thr1550Ile variant (sometimes called p.Thr1571Ile) in BRCA1 has been reported in 1 pediatric individual with hyperdiploid acute lymphoblastic leukemia (PMID: 26580448), and was absent from large population studies. This variant has also been reported as a VUS in ClinVar (Variation ID: 55251). In vitro functional studies provide some evidence that the p.Thr1550Ile variant may not reduce gene expression (PMID: 28781887). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The Threonine (Thr) at position 1550 is not conserved in mammals or evolutionary distant species, raising the possibility that a change at this position may be tolerated. Additional computational prediction tools suggest that this variant will affect binding to another protein (PMID: 23704879). In summary, the clinical significance of the p.Thr1550Ile variant is uncertain. ACMG/AMP Criteria applied: PM2, BS3_Supporting (Richards 2015).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.