Submissions for variant NM_000059.4(BRCA2):c.3119C>T (p.Thr1040Ile)

dbSNP: rs587781475

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129423	SCV000184193	uncertain significance	Hereditary cancer-predisposing syndrome	2013-12-09	criteria provided, single submitter	clinical testing	The p.T1040I variant (also known as c.3119C>T and 3347C>T) is located in coding exon 10 of the BRCA2 gene. This alteration results from a C to T substitution at nucleotide position 3119. The threonine at codon 1040 is replaced by isoleucine, an amino acid with similar properties. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. Based on protein sequence alignment, 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 p.T1040I remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000129423	SCV001353898	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-23	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1040 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129423	SCV003851700	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998260	SCV005624383	uncertain significance	not provided	2024-05-23	criteria provided, single submitter	clinical testing	The BRCA2 c.3119C>T (p.Thr1040Ile) variant has been reported in the published literature to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). To the best of our knowledge, this variant has not been reported in individuals with BRCA2-related disorders. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.