NM_002485.5:c.468A>C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_002485.5(NBN):āc.468A>Cā(p.Lys156Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,612,142 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002485.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000151 AC: 38AN: 251210Hom.: 1 AF XY: 0.0000884 AC XY: 12AN XY: 135794
GnomAD4 exome AF: 0.0000288 AC: 42AN: 1459956Hom.: 1 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 726426
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74370
ClinVar
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Uncertain:3
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This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 156 of the NBN protein (p.Lys156Asn). This variant is present in population databases (rs730881858, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with breast cancer and/or clinical features of NBN-related conditions (PMID: 31206626, 36346689, 38446568). ClinVar contains an entry for this variant (Variation ID: 182729). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
not provided Uncertain:3
The frequency of this variant in the general population, 0.0011 (38/34566 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer, as well as unaffected individuals (PMID: 31206626 (2019)), colorectal cancer (PMID: 33359728 (2022)), endometrial adenocarcinoma and synchronous ovarian endometrioid adenocarcinoma (PMID: 32945065 (2021)). 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. -
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In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer or early-onset colorectal cancer, but also in healthy controls (Weitzel et al., 2019; Dharwadkar et al., 2020); This variant is associated with the following publications: (PMID: 32945065, 33359728, 31206626) -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not specified Uncertain:1
Variant summary: NBN c.468A>C (p.Lys156Asn) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251210 control chromosomes, exclusively at a frequency of 0.0011 within the Latino subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (0.00015 vs 0.0025), allowing no conclusion about variant significance. c.468A>C has been reported in the literature in an individual with breast cancer, but also healthy controls (e.g. Weitzel_2019). This report does not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely benign (n=1) and uncertain significance (n=5). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at