ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.16C>T (p.Pro6Ser) (rs730881859)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212724 SCV000211463 uncertain significance not provided 2018-07-06 criteria provided, single submitter clinical testing This variant is denoted NBN c.16C>T at the cDNA level, p.Pro6Ser (P6S) at the protein level, and results in the change of a Proline to a Serine (CCC>TCC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. NBN Pro6Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). NBN Pro6Ser is located in the FHA domain (Damiola 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NBN Pro6Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160798 SCV000216638 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-16 criteria provided, single submitter clinical testing The p.P6S variant (also known as c.16C>T), located in coding exon 1 of the NBN gene, results from a C to T substitution at nucleotide position 16. The proline at codon 6 is replaced by serine, an amino acid with similar properties. This amino acid position is well 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.
Invitae RCV000197183 SCV000254767 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 6 of the NBN protein (p.Pro6Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs730881859, ExAC 0.006%). This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 182731). 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 serine 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.
Color Health, Inc RCV000160798 SCV000903101 likely benign Hereditary cancer-predisposing syndrome 2017-01-04 criteria provided, single submitter clinical testing
Natera, Inc. RCV000197183 SCV001461788 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2020-09-16 no assertion criteria provided clinical testing

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