rs863224714
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM5BP4
The NM_002485.5(NBN):c.1484C>T(p.Pro495Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P495S) has been classified as Likely benign.
Frequency
Consequence
NM_002485.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NBN | NM_002485.5 | c.1484C>T | p.Pro495Leu | missense_variant | 11/16 | ENST00000265433.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.1484C>T | p.Pro495Leu | missense_variant | 11/16 | 1 | NM_002485.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152066Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461226Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 726920
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152066Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74280
ClinVar
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 22, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 495 of the NBN protein (p.Pro495Leu). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 216564). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 03, 2020 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 22, 2022 | The frequency of this variant in the general population, 0.000032 (1/31372 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. This variant has been reported in an individual with colon cancer (PMID: 27978560 (2016)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/NBN)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 25, 2022 | Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colon cancer (Pearlman 2017); This variant is associated with the following publications: (PMID: 27978560) - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 26, 2023 | The c.1484C>T (p.P495L) alteration is located in exon 11 (coding exon 11) of the NBN gene. This alteration results from a C to T substitution at nucleotide position 1484, causing the proline (P) at amino acid position 495 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 14, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 24, 2022 | Variant summary: NBN c.1484C>T (p.Pro495Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250652 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1484C>T has been reported in the literature as a VUS in at-least one mismatch repair (MMR) proficient individual from a cohort undergoing multigene panel testing for early onset colorectal cancer (example, Pearlman_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome or NBN-related cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Aplastic anemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 20, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at