ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212753 SCV000149695 uncertain significance not provided 2020-08-03 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with ovarian, colon, and prostate cancer (Ramus 2015, Hampel 2018, Martin-Morales 2018, Paulo 2018); This variant is associated with the following publications: (PMID: 30256826, 26315354, 29596542, 29659569)
Ambry Genetics RCV000115786 SCV000213561 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-17 criteria provided, single submitter clinical testing The p.S667P variant (also known as c.1999T>C), located in coding exon 13 of the NBN gene, results from a T to C substitution at nucleotide position 1999. The serine at codon 667 is replaced by proline, an amino acid with similar properties. In one study, this alteration was observed in 3 of 3236 cases with invasive epithelial ovarian cancer and in 2 of 3431 controls (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107). This amino acid position is not well conserved in available vertebrate species, and proline is the reference amino acid in other 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 RCV000230585 SCV000287461 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2020-11-02 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 or colorectal cancer, as well as unaffected individuals (PMID: 26315354, 29596542). 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.
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
Counsyl RCV000230585 SCV000794192 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2017-09-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212753 SCV000888331 uncertain significance not provided 2020-07-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115786 SCV000902742 likely benign Hereditary cancer-predisposing syndrome 2015-07-29 criteria provided, single submitter clinical testing
Baylor Genetics RCV001328956 SCV001520211 uncertain significance Aplastic anemia 2019-02-11 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212753 SCV001746045 likely benign not provided 2021-05-01 criteria provided, single submitter clinical testing

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