Submissions for variant NM_007294.4(BRCA1):c.3172A>G (p.Ile1058Val)

dbSNP: rs1064795478

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479949	SCV000571315	uncertain significance	not provided	2018-06-29	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.3172A>G at the cDNA level, p.Ile1058Val (I1058V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). Using alternate nomenclature, this variant would be defined as BRCA1 3291A>G. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA1 Ile1058Val was not observed in large population cohorts (Lek 2016). This variant is located in the DNA Binding domain and the RAD51 binding domain (Chen 1998, Narod 2004). 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 Ile1058Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000571167	SCV000665909	uncertain significance	Hereditary cancer-predisposing syndrome	2017-02-14	criteria provided, single submitter	clinical testing	The p.I1058V variant (also known as c.3172A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 3172. The isoleucine at codon 1058 is replaced by valine, an amino acid with highly 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	RCV000571167	SCV000912150	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-30	criteria provided, single submitter	clinical testing
Invitae	RCV001212358	SCV001383941	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-03-09	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 421966). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1058 of the BRCA1 protein (p.Ile1058Val).
Molecular Endocrinology Laboratory, Christian Medical College	RCV001770373	SCV002003985	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000571167	SCV003852485	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).