ClinVar Genomic variation as it relates to human health

This is a nonsense variant, leading to the appearance of a stop codon at the position 714 of the NBN protein. It is expected to result in an absent or disrupted protein product. Truncating variants in NBN gene are known to be pathogenic. This particular variant has been as been described in the literature breast cancer patients (PMID: 29093764). The mutation database ClinVar contains several entries for this variant (Variation ID: 182737).

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast, ovarian, or other cancer (Jian et al., 2017; Singh et al., 2018; Carlo et al., 2020; Fostira et al., 2020; Dorling et al., 2021; Puccini et al., 2022; Anacleiro et al., 2023); This variant is associated with the following publications: (PMID: 31159747, 29922827, 29093764, 29470806, 30676620, 34426522, 29625052, 31589614, 33630411, 26681312, 37065479, 31300551, 36139606, 35833951, 33804961, 31794323, 33471991, 27535533, Ayaz2022[article])

The observed stop gained variant c.2140C>T(p.Arg714Ter) in NBN gene has been reported previously in homozygous and heterozygous state in individuals with Nijmegen breakage syndrome (NBS), breast cancer and/or ovarian cancer (Jian W, et al., 2017, Carlo MI, et al., 2020). The c.2140C>T variant has 0.002% allele frequency in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (Multiple submissions). Computational evidence (Mutation Taster - Disease causing) predicts damaging effect on protein structure and function for this variant. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (Varon R, et al., 2006). For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed.

Variant summary: NBN c.2140C>T (p.Arg714X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.4e-05 in 246018 control chromosomes in gnomAD. This frequency is not higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (2.4e-05 vs 2.50E-03), allowing no conclusion about variant significance. The c.2140C>T variant has been reported in the literature in individuals affected with cancer (Susswein_2015, Jian_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

The p.R714* pathogenic mutation (also known as c.2140C>T), located in coding exon 14 of the NBN gene, results from a C to T substitution at nucleotide position 2140. This changes the amino acid from an arginine to a stop codon within coding exon 14. This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). It has also been reported in 1/120 Chinese patients with breast cancer and was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Jian W et al. Hered Cancer Clin Pract. 2017 Oct;15:19). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

This sequence change creates a premature translational stop signal (p.Arg714*) in the NBN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). This variant is present in population databases (rs730881864, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 182737). For these reasons, this variant has been classified as Pathogenic.

Variant classified as Pathogenic and reported on 04-24-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.