Submissions for variant NM_000059.4(BRCA2):c.6289A>G (p.Thr2097Ala)

gnomAD frequency: 0.00001  dbSNP: rs587781965

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130344	SCV000185195	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-03	criteria provided, single submitter	clinical testing	The p.T2097A variant (also known as c.6289A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 6289. The threonine at codon 2097 is replaced by alanine, an amino acid with similar properties. In one study, this alteration was seen in 2/7400 Czech high risk breast and/or ovarian cancer families (Machackova E et al. Klin Onkol, 2019;32:51-71). 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	RCV000130344	SCV000688975	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001062323	SCV001227117	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-04-17	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2097 of the BRCA2 protein (p.Thr2097Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 141723). 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 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237739	SCV002010341	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130344	SCV003852397	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).
GenomeConnect - Invitae Patient Insights Network	RCV001535459	SCV001749378	not provided	BRCA2-related disorder		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 04-25-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.