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

gnomAD frequency: 0.00001  dbSNP: rs80357489

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000047479	SCV000075492	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 483 of the BRCA1 protein (p.Ile483Thr). This variant is present in population databases (rs80357489, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 54255). 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%. 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	2022-04-07	criteria provided, single submitter	clinical testing	The p.I483T variant (also known as c.1448T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 1448. The isoleucine at codon 483 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000575874	SCV000909586	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-04	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 483 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). To our knowledge, functional studies have not been reported for this variant. This variant has been report in a multifactorial analysis with likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.0673 and 1.4557, respectively (PMID: 31131967). This variant has been identified in 1/31406 chromosomes 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000575874	SCV003851292	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Sharing Clinical Reports Project (SCRP)	RCV000083170	SCV000115244	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2008-03-19	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000083170	SCV000144098	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing