Submissions for variant NM_000059.4(BRCA2):c.4940C>T (p.Thr1647Ile)

dbSNP: rs1593903891

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001348610	SCV001542917	uncertain significance	Hereditary breast ovarian cancer syndrome	2020-05-06	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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in an individual with breast cancer (Invitae). However, in that individual a pathogenic allele was also identified in BRCA2, which suggests that this c.4940C>T variant was not the primary cause of disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 1647 of the BRCA2 protein (p.Thr1647Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine.
Ambry Genetics	RCV002341727	SCV002642721	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-24	criteria provided, single submitter	clinical testing	The p.T1647I variant (also known as c.4940C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 4940. The threonine at codon 1647 is replaced by isoleucine, 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002341727	SCV003852220	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).