Submissions for variant NM_000059.4(BRCA2):c.6764C>T (p.Thr2255Ile)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002303005	SCV002589551	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-07-23	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 2255 of the BRCA2 protein (p.Thr2255Ile). 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 BRCA2 protein function. This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics	RCV002363749	SCV002661681	uncertain significance	Hereditary cancer-predisposing syndrome	2016-12-13	criteria provided, single submitter	clinical testing	The p.T2255I variant (also known as c.6764C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 6764. The threonine at codon 2255 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not well 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002363749	SCV003847431	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).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV005232944	SCV005872788	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing	Classification criteria: BP1_Strong
Mendelics	RCV005232945	SCV005880332	uncertain significance	Hereditary cancer	2025-02-26	criteria provided, single submitter	clinical testing	The available evidence is insufficient to conclusively determine the role of this variant. Therefore, it is classified as a Variant of Uncertain Significance.