rs730881857

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_002485.5(NBN):ā€‹c.2117C>Gā€‹(p.Ser706*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000248 in 1,611,854 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 (ā˜…ā˜…). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

NBN
NM_002485.5 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 4.95
Variant links:
Genes affected
NBN (HGNC:7652): (nibrin) Mutations in this gene are associated with Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. The encoded protein is a member of the MRE11/RAD50 double-strand break repair complex which consists of 5 proteins. This gene product is thought to be involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-89943320-G-C is Pathogenic according to our data. Variant chr8-89943320-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 182728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NBNNM_002485.5 linkuse as main transcriptc.2117C>G p.Ser706* stop_gained 14/16 ENST00000265433.8 NP_002476.2 O60934

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NBNENST00000265433.8 linkuse as main transcriptc.2117C>G p.Ser706* stop_gained 14/161 NM_002485.5 ENSP00000265433.4 O60934

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152082
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251314
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135822
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1459772
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726318
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152082
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74274
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 25, 2018Variant 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. -
Likely pathogenic, criteria provided, single submitterclinical testingCounsylDec 21, 2015- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024This 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. Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). This variant is present in population databases (rs730881857, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with prostate cancer and bladder cancer (PMID: 22864661). ClinVar contains an entry for this variant (Variation ID: 182728). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 06, 2024The p.S706* pathogenic mutation (also known as c.2117C>G), located in coding exon 14 of the NBN gene, results from a C to G substitution at nucleotide position 2117. This changes the amino acid from a serine to a stop codon within coding exon 14. This mutation has previously been reported in a family with hereditary prostate cancer (Zuhlke KA et al. Fam. Cancer. 2012 Dec;11:595-600) and in an individual with a personal history of breast cancer (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). 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. -
Likely pathogenic, criteria provided, single submittercurationSema4, Sema4Feb 19, 2021- -
Aplastic anemia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 28, 2024- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxMar 08, 2024Nonsense 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 a personal and/or family history of breast, prostate, and other cancers (PMID: 26681312, 22864661, 29625052); This variant is associated with the following publications: (PMID: 23149842, 26681312, 22864661, 32875559, 29625052, 30590007, 33077847, 35434237, Mendhiratta2023[abstract], 29922827, 36451132, 33047316, 36495689) -
NBN-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesSep 05, 2023The NBN c.2117C>G variant is predicted to result in premature protein termination (p.Ser706*). This patient is heterozygous in the NBN gene for a sequence variant defined as c.2117C>G, which is predicted to result in premature protein termination (p.Ser706*). This variant has been reported in a family with prostate cancer; however, the variant did not segregate with disease (Zuhlke et al. 2012. PubMed ID: 22864661). This variant has also been reported in individuals with melanoma and breast cancer (Aoude et al. 2020. PubMed ID: 33077847; Huang et al. 2018. PubMed ID: 29625052; Susswein et al. 2016. PubMed ID: 26681312). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-90955548-G-C). Nonsense variants in NBN are expected to be pathogenic for autosomal recessive disease, and this variant has been classified as pathogenic or likely pathogenic by multiple submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182728/). This variant is interpreted as pathogenic. -
Malignant tumor of breast;C0398791:Microcephaly, normal intelligence and immunodeficiency Other:1
not provided, no classification providedphenotyping onlyGenomeConnect - Invitae Patient Insights Network-Variant interpreted as Pathogenic and reported on 08-28-2017 by Ambry Genetics. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
42
DANN
Uncertain
1.0
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Pathogenic
0.98
D
Vest4
0.91
GERP RS
5.9

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs730881857; hg19: chr8-90955548; API