ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.73G>A (p.Val25Ile) (rs587781748)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129954 SCV000184778 likely benign Hereditary cancer-predisposing syndrome 2017-06-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Color RCV000129954 SCV000911424 likely benign Hereditary cancer-predisposing syndrome 2016-07-24 criteria provided, single submitter clinical testing
Counsyl RCV000232974 SCV000798190 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-02-27 criteria provided, single submitter clinical testing
GeneDx RCV000656923 SCV000211446 uncertain significance not provided 2018-06-22 criteria provided, single submitter clinical testing This variant is denoted NBN c.73G>A at the cDNA level, p.Val25Ile (V25I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant was identified in 1/3,236 cases and absent in 3,431 controls in an ovarian cancer case-control study (Ramus 2015), and was observed in at least three breast cancer patients (Hauke 2018). NBN Val25Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the FHA domain (Damiola 2014). 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 NBN Val25Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000232974 SCV000287482 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-09-13 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 25 of the NBN protein (p.Val25Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs587781748, ExAC 0.006%). This variant has been reported in an individual affected with ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 141440). 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 RCV000212726 SCV000601700 uncertain significance not specified 2016-08-19 criteria provided, single submitter clinical testing

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