ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.2117C>G (p.Ser706Ter) (rs730881857)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212754 SCV000211460 pathogenic not provided 2018-04-24 criteria provided, single submitter clinical testing This pathogenic variant is denoted NBN c.2117C>G at the cDNA level and p.Ser706Ter (S706X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. NBN Ser706Ter has been reported in a European male with early onset prostate cancer and showed partial co-segregation among affected family members (Zuhlke 2012). We consider this variant to be pathogenic.
Ambry Genetics RCV000160795 SCV000217454 pathogenic Hereditary cancer-predisposing syndrome 2018-06-25 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Rarity in general population databases (dbsnp, esp, 1000 genomes)
Counsyl RCV000409031 SCV000485485 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2015-12-21 criteria provided, single submitter clinical testing
Color RCV000160795 SCV000537662 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Invitae RCV000409031 SCV000553078 pathogenic Microcephaly, normal intelligence and immunodeficiency 2019-12-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser706*) in the NBN gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs730881857, ExAC 0.001%). This variant has been observed in a family with prostate cancer and bladder cancer (PMID: 22864661). ClinVar contains an entry for this variant (Variation ID: 182728). Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000409031 SCV000917858 pathogenic Microcephaly, normal intelligence and immunodeficiency 2018-06-25 criteria provided, single submitter clinical testing Variant summary: NBN c.2117C>G (p.Ser706X) results in a premature termination codon, predicted to cause a truncation of the encoded protein in a highly conserved region of NBN near the MRE11 binding site due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 247890 control chromosomes (gnomAD and controls). The variant, c.2117C>G, has been reported in the literature in individuals affected with Hereditary Breast cancer, along with one family, Zuhkle_2012, in whom the variant was reported to partially co-segregate with prostate cancer. Individuals who are heterozygous for NBN mutations are clinically asymptomatic, but may display an elevated risk for certain cancers including, but not limited to, ovarian and prostate cancer as well as various lymphoid malignancies. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.