ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7010C>T (p.Thr2337Ile) (rs80358927)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130807 SCV000185703 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113691 SCV000147000 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000130807 SCV000911244 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-09 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000113691 SCV000733291 likely benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
GeneDx RCV000656800 SCV000210412 uncertain significance not provided 2018-04-26 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7010C>T at the cDNA level, p.Thr2337Ile (T2337I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). Using alternate nomenclature, this variant would be defined as BRCA2 7238C>T. This variant was observed in at least two individuals with a personal and/or family history of breast and/or ovarian cancer (Gomez-Garcia 2005, van der Hout 2006). BRCA2 Thr2337Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Thr2337Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000203621 SCV000073133 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 2337 of the BRCA2 protein (p.Thr2337Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs80358927, ExAC 0.002%). This variant has been reported in individuals undergoing testing for hereditary breast and ovarian cancer (PMID: 15800311, 16683254, 27376475), and in individuals in the Breast Cancer Information Core database (PMID: 10923033). However, in one of these individuals a pathogenic variant was also identified in BRCA1, which suggests that this c.7010C>T BRCA2 variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 52248). 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 isoleucine 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. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000045120 SCV000600730 uncertain significance not specified 2016-12-05 criteria provided, single submitter clinical testing

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