Submissions for variant NM_000059.4(BRCA2):c.2039C>T (p.Thr680Ile)

dbSNP: rs1566226005

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000772333	SCV000905493	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000772333	SCV001174837	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-29	criteria provided, single submitter	clinical testing	The p.T680I variant (also known as c.2039C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 2039. The threonine at codon 680 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is poorly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001201832	SCV001372923	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-04-11	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 680 of the BRCA2 protein (p.Thr680Ile). 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: 628047). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000772333	SCV003846463	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).
All of Us Research Program, National Institutes of Health	RCV004802419	SCV005424313	uncertain significance	BRCA2-related cancer predisposition	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 680 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has not been identified 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.