Submissions for variant NM_002485.5(NBN):c.547G>A (p.Ala183Thr)

gnomAD frequency: 0.00003  dbSNP: rs151070415

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475501	SCV000553127	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2024-11-12	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 183 of the NBN protein (p.Ala183Thr). This variant is present in population databases (rs151070415, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 31512090). ClinVar contains an entry for this variant (Variation ID: 411786). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV000570581	SCV000662690	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-12	criteria provided, single submitter	clinical testing	The p.A183T variant (also known as c.547G>A), located in coding exon 5 of the NBN gene, results from a G to A substitution at nucleotide position 547. The alanine at codon 183 is replaced by threonine, an amino acid with similar properties. This variant has been reported in 1/81 male breast cancer patients who had multi-gene panel testing (Scarpitta R et al. Breast Cancer Res Treat, 2019 Dec;178:557-564). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586067	SCV000697973	uncertain significance	not provided	2016-10-06	criteria provided, single submitter	clinical testing	Variant summary: The NBN c.547G>A (p.Ala183Thr) variant indicated to be located at the last amino position of the BRCT domain (via InterPro) causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121276, which does not exceed the estimated maximal expected allele frequency for a pathogenic NBN variant of 1/400. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Therefore, until additional information becomes available (ie, clinical and/or functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance."
GeneDx	RCV000586067	SCV001770478	uncertain significance	not provided	2023-03-17	criteria provided, single submitter	clinical testing	Not observed at 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 an individual with breast cancer (Scarpitta et al., 2019); This variant is associated with the following publications: (PMID: 24894818, 16188882, 34072463, 31512090)
Genome-Nilou Lab	RCV000475501	SCV002045179	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586067	SCV005623896	uncertain significance	not provided	2024-01-17	criteria provided, single submitter	clinical testing	The NBN c.547G>A (p.Ala183Thr) variant has been reported in the published literature in individuals with male breast cancer (PMID: 31512090 (2019)) and breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/NBN)). This variant has also been identified in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/NBN)). The frequency of this variant in the general population, 0.000026 (3/113650 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc.	RCV000475501	SCV002078652	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-07-03	no assertion criteria provided	clinical testing