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

gnomAD frequency: 0.00001  dbSNP: rs80357076

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195394	SCV000076631	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1550 of the BRCA1 protein (p.Thr1550Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 10923033, 26580448). This variant is also known as T1571I. ClinVar contains an entry for this variant (Variation ID: 55251). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 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	2023-07-24	criteria provided, single submitter	clinical testing	The p.T1550I variant (also known as c.4649C>T), located in coding exon 13 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4649. The threonine at codon 1550 is replaced by isoleucine, an amino acid with similar properties. This alteration has been predicted to be 'likely not pathogenic' based on functional data from a transcriptional activation luciferase reporter assay (Woods NT et al. NPJ Genom Med. 2016;1. pii: 16001). However, in another study, this alteration was associated with altered phosphorylation of a putative kinase binding motif using the NetworKIN algorithm (Tram E et al. PLoS ONE 2013; 8(5):e62468). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000048618	SCV000210182	uncertain significance	not provided	2023-01-19	criteria provided, single submitter	clinical testing	Observed in individuals with pediatric cancer (Zhang et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in large population cohorts (gnomAD); Published functional studies suggest this variant has no damaging effect: transcriptional activiation activity comparable to wildtype (Woods et al., 2016; Fernandes et al., 2019, Iversen et al., 2022); Also known as 4768C>T; This variant is associated with the following publications: (PMID: 15385441, 23704879, 19276368, 28781887, 31131967, 29884841, 31911673, 32377563, 35665744, 11301010, 9774970, 10220405, 31853058, 30765603, 26580448)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000048618	SCV000296308	uncertain significance	not provided	2023-05-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000013 (2/152198 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with pediatric leukemia (PMID: 26580448 (2015)). It is predicted to abolish a BRCA1 phosphorylation site in silico, but the effect of the predicted change on BRCA1 function is unknown (PMID: 23704879 (2013)). Functional studies show that this variant has a higher activity than a wild type control in an in vitro transcription activation assay (PMIDs: 28781887 (2016) and 30765603 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Counsyl	RCV000112373	SCV000488717	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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 Diagnostics, LLC DBA Color Health	RCV000129109	SCV000688507	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-21	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1550 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A transcription activation assay using transiently transfected mammalian cell has reported this variant as functional (PMID: 28781887). This variant has been reported in one individual affected with leukemia (PMID: 26580448). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.256 and 1.0595, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248951	SCV001422731	uncertain significance	not specified	2020-01-22	criteria provided, single submitter	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).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000112373	SCV001428451	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2019-04-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001248951	SCV001442613	uncertain significance	not specified	2020-10-08	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4649C>T (p.Thr1550Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251282 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4649C>T has been reported in the literature in an individual affected with hyperdiploid ALL (acute lymphoblastic leukemia) (Zhang_2015). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. In transcriptional activation luciferase reporter assays, the variant was found to have similar activity that of wild type (Woods_2016). Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000112373	SCV001482788	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2019-07-17	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics	RCV002477174	SCV002785343	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-08-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000112373	SCV004817646	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1550 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A transcription activation assay using transiently transfected mammalian cell has reported this variant as functional (PMID: 28781887). This variant has been reported in one individual affected with leukemia (PMID: 26580448). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.256 and 1.0595, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112373	SCV000145139	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing