Submissions for variant NM_002485.5(NBN):c.16C>T (p.Pro6Ser)

dbSNP: rs730881859

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212724	SCV000211463	uncertain significance	not provided	2025-02-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29535844, 24894818, 36346689)
Ambry Genetics	RCV000160798	SCV000216638	likely benign	Hereditary cancer-predisposing syndrome	2024-07-17	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197183	SCV000254767	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2024-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 6 of the NBN protein (p.Pro6Ser). This variant is present in population databases (rs730881859, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 182731). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine 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.
Genome-Nilou Lab	RCV000197183	SCV002046010	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467264	SCV004199541	uncertain significance	Aplastic anemia	2024-01-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700496	SCV005202206	uncertain significance	not specified	2024-07-01	criteria provided, single submitter	clinical testing	Variant summary: NBN c.16C>T (p.Pro6Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 245282 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.16C>T has been reported in the literature in an individual affected with cancer without clinical information (Belhadj_2023). 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. The following publication has been ascertained in the context of this evaluation (PMID: 36346689). ClinVar contains an entry for this variant (Variation ID: 182731). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212724	SCV005623884	uncertain significance	not provided	2024-05-27	criteria provided, single submitter	clinical testing	The NBN c.16C>T (p.Pro6Ser) variant has been reported in the published literature as a somatic variant in a case of intramucosal carcinoma (PMID: 29535844 (2018)). The frequency of this variant in the general population, 0.000027 (3/109680 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc.	RCV000197183	SCV001461788	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-09-16	no assertion criteria provided	clinical testing