ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1999T>C (p.Ser667Pro) (rs587780091)

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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 RCV000115786 SCV000213561 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000115786 SCV000902742 likely benign Hereditary cancer-predisposing syndrome 2015-07-29 criteria provided, single submitter clinical testing
Counsyl RCV000230585 SCV000794192 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2017-09-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515337 SCV000611486 uncertain significance Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000212753 SCV000149695 uncertain significance not provided 2018-07-06 criteria provided, single submitter clinical testing This variant is denoted NBN c.1999T>C at the cDNA level, p.Ser667Pro (S667P) at the protein level, and results in the change of a Serine to a Proline (TCT>CCT). This variant was identified in 3/3,236 cases and 2/3,431 controls in an ovarian cancer case-control study (Ramus 2015). NBN Ser667Pro was observed at an allele frequency of 0.012% (4/34,398) in individuals of Latino ancestry 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 NBN Ser667Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000230585 SCV000287461 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 667 of the NBN protein (p.Ser667Pro). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and proline. This variant is present in population databases (rs587780091, ExAC 0.03%). This variant has been reported in individuals affected with ovarian cancer, as well as unaffected individuals (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 127863). 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 proline 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212753 SCV000888331 uncertain significance not provided 2018-06-27 criteria provided, single submitter clinical testing

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