Submissions for variant NM_000059.4(BRCA2):c.3260C>T (p.Thr1087Ile)

dbSNP: rs1555283123

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000582950	SCV000688794	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000582950	SCV001180864	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-25	criteria provided, single submitter	clinical testing	The p.T1087I variant (also known as c.3260C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 3260. The threonine at codon 1087 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	RCV001226691	SCV001399012	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-06-18	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 1087 of the BRCA2 protein (p.Thr1087Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 18284688). ClinVar contains an entry for this variant (Variation ID: 491236). 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	RCV000582950	SCV003851813	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).
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003234785	SCV003932715	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	The p.T1087I variant (also known as c.3260C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 3260. The threonine at codon 1087 is replaced by isoleucine, an amino acid with similar properties.In-silico predictions showed benign computational verdict based on 8 benign predictions from BayesDel_addAF, DANN, EIGEN, FATHMM-MKL, MVP, MutationTaster, PrimateAI and SIFT vs 1 pathogenic prediction from M-CAP and the position is not highly conserved. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. Therefore, this variant is classified as on uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004802267	SCV005424372	uncertain significance	BRCA2-related cancer predisposition	2024-09-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV005000347	SCV005624387	uncertain significance	not provided	2024-08-08	criteria provided, single submitter	clinical testing	The BRCA2 c.3260C>T (p.Thr1087Ile) 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)). 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.