ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.2252C>T (p.Thr751Ile)

gnomAD frequency: 0.00001  dbSNP: rs398122743
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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 RCV000165229 SCV000215943 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-15 criteria provided, single submitter clinical testing The p.T751I variant (also known as c.2252C>T and 2480C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 2252. The threonine at codon 751 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. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort. This amino acid position is poorly conserved in available vertebrate species and isoleucine is the reference amino acid in many 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.T751I remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000704300 SCV000833244 uncertain significance Hereditary breast ovarian cancer syndrome 2021-04-21 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 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. This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 91772). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 751 of the BRCA2 protein (p.Thr751Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine.
Color Diagnostics, LLC DBA Color Health RCV000165229 SCV000906036 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-30 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000165229 SCV003846606 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).
Myriad Genetics, Inc. RCV000077680 SCV004931053 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 2024-03-26 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
CeGaT Center for Human Genetics Tuebingen RCV004597740 SCV005092019 likely benign not provided 2024-07-01 criteria provided, single submitter clinical testing BRCA2: PM2:Supporting, BP1, BP4
Quest Diagnostics Nichols Institute San Juan Capistrano RCV004597740 SCV005624350 uncertain significance not provided 2023-12-14 criteria provided, single submitter clinical testing The BRCA2 c.2252C>T (p.Thr751Ile) 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)). The frequency of this variant in the general population, 0.000032 (1/31398 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.
Sharing Clinical Reports Project (SCRP) RCV000077680 SCV000109483 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2011-03-09 no assertion criteria provided clinical testing

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