Submissions for variant NM_007294.4(BRCA1):c.2534T>C (p.Ile845Thr)

dbSNP: rs397508976

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410162	SCV000489498	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-10-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000561022	SCV000661128	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-17	criteria provided, single submitter	clinical testing	The p.I845T variant (also known as c.2534T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 2534. The isoleucine at codon 845 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.
Invitae	RCV001360641	SCV001556568	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-10-31	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: 54593). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is present in population databases (rs397508976, gnomAD 0.0009%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 845 of the BRCA1 protein (p.Ile845Thr).
Color Diagnostics, LLC DBA Color Health	RCV000561022	SCV001735772	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-08	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 845 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251044 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	RCV000561022	SCV003847598	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).