Submissions for variant NM_002485.5(NBN):c.596C>G (p.Pro199Arg)

gnomAD frequency: 0.00001  dbSNP: rs730881844

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726896	SCV000211439	uncertain significance	not provided	2024-08-27	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; This variant is associated with the following publications: (PMID: 22491912, 26898890, 29522266, 34326862, 33471991, 36346689, 24894818, 32268276)
Ambry Genetics	RCV000160780	SCV000217157	likely benign	Hereditary cancer-predisposing syndrome	2022-10-04	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	RCV000205060	SCV000261479	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 199 of the NBN protein (p.Pro199Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer or prostate cancer (PMID: 22491912, 26898890, 32268276, 34326862). ClinVar contains an entry for this variant (Variation ID: 182713). 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.
Illumina Laboratory Services, Illumina	RCV000205060	SCV000475298	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Eurofins Ntd Llc (ga)	RCV000726896	SCV000703953	uncertain significance	not provided	2017-01-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000726896	SCV000889552	uncertain significance	not provided	2017-12-07	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000205060	SCV002045168	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002229765	SCV002511645	uncertain significance	not specified	2024-03-11	criteria provided, single submitter	clinical testing	Variant summary: NBN c.596C>G (p.Pro199Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250342 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.596C>G has been reported in the literature in individuals affected with cancer and in unaffected controls (e.g. Mateju_2012, Belhadj_2023). These reports do 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 publications have been ascertained in the context of this evaluation (PMID: 22491912, 36346689). ClinVar contains an entry for this variant (Variation ID: 182713). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV002229765	SCV002518361	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160780	SCV002536698	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-22	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000726896	SCV004155991	uncertain significance	not provided	2022-07-01	criteria provided, single submitter	clinical testing	NBN: PM2, BP1
Baylor Genetics	RCV003474833	SCV004199567	uncertain significance	Aplastic anemia	2023-12-18	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000205060	SCV002078645	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-10-19	no assertion criteria provided	clinical testing