rs730881864
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_002485.5(NBN):c.2140C>T(p.Arg714Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R714R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_002485.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NBN | NM_002485.5 | c.2140C>T | p.Arg714Ter | stop_gained | 14/16 | ENST00000265433.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.2140C>T | p.Arg714Ter | stop_gained | 14/16 | 1 | NM_002485.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151998Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251258Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135786
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461318Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 726990
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151998Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74236
ClinVar
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Pathogenic:5Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The c.2140C>T (p.Arg714Ter) variant in NBN gene has been reported previously in individuals affected with breast cancer or ovarian cancer.(Jian et al,2017).This is a nonsense variant, leading to the appearance of a stop codon at the position 714 of the NBN protein. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The variant is novel (not in any individuals) in 1000 Genomes and allele frequency 0.00002388 is reported in gnomAD. The nucleotide change in NBN is predicted as conserved by GERP++ and PhyloP across 100 vertebrates.. 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. For these reasons, this variant has been classified as Pathogenic . - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 28, 2017 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 09, 2018 | 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. - |
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 06, 2023 | 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]) - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 06, 2022 | 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. - |
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 12, 2022 | - - |
Aplastic anemia;C0023449:Acute lymphoid leukemia;C0398791:Microcephaly, normal intelligence and immunodeficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 19, 2021 | - - |
Aplastic anemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 12, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at