ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.2999T>C (p.Ile1000Thr) (rs374769365)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130892 SCV000185801 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-18 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 RCV000168562 SCV000210300 likely benign not specified 2017-09-21 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
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 2019-10-18 criteria provided, single submitter clinical testing
Invitae RCV000257906 SCV000549689 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-01 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1000 of the BRCA2 protein (p.Ile1000Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 142073). 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 threonine 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. 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.
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 Health, Inc RCV000130892 SCV000905819 likely benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
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.

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