Submissions for variant NM_000059.4(BRCA2):c.2999T>C (p.Ile1000Thr)

dbSNP: rs374769365

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130892	SCV000185801	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-27	criteria provided, single submitter	clinical testing	The p.I1000T variant (also known as c.2999T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 2999. The isoleucine at codon 1000 is replaced by threonine, 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.
GeneDx	RCV000587614	SCV000210300	likely benign	not provided	2019-10-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768593	SCV000219323	uncertain significance	Breast and/or ovarian cancer	2017-05-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587614	SCV000296680	uncertain significance	not provided	2022-08-16	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in the published literature. It also has not been reported in large, multi-ethnic general populations (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.
Invitae	RCV000257906	SCV000549689	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587614	SCV000694659	uncertain significance	not provided	2016-06-06	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.2999T>C (p.Ile1000Thr) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome. This variant was absent in 120332 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000130892	SCV000905819	likely benign	Hereditary cancer-predisposing syndrome	2015-11-17	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130892	SCV003850301	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353934	SCV000591842	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Ile1000Thr variant was not identified in the literature, nor was it identified in the dbSNP, 1000 Genomes Project, NHLBI Exome Sequencing Project, HGMD, LOVD, COSMIC, UMD, or BIC databases. The p.Ile1000 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD) do not suggest a high likelihood of impact of the variant amino acid to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.