Submissions for variant NM_002485.5(NBN):c.2146A>G (p.Asn716Asp)

gnomAD frequency: 0.00830  dbSNP: rs72563785

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000121615	SCV000170644	benign	not specified	2013-10-23	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000128986	SCV000172876	benign	Hereditary cancer-predisposing syndrome	2014-07-28	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Invitae	RCV000168432	SCV000219129	benign	Microcephaly, normal intelligence and immunodeficiency	2024-01-31	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000128986	SCV000267062	likely benign	Hereditary cancer-predisposing syndrome	2016-02-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000168432	SCV000475286	benign	Microcephaly, normal intelligence and immunodeficiency	2018-01-12	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Genetic Services Laboratory, University of Chicago	RCV000121615	SCV000595913	benign	not specified	2015-08-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000121615	SCV000601685	benign	not specified	2021-06-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589914	SCV000697961	benign	not provided	2016-05-02	criteria provided, single submitter	clinical testing	Variant summary: The c.2146A>G variant affects a conserved nucleotide, resulting in amino acid change from Asn to Asp. 3/4 in-silico tools predict this variant to be benign. This variant is found in 295/121388 control chromosomes (including 5 homozygotes) at a frequency of 0.0024302. It was predominantly observed in the African subpopulation at a frequency of 2.7% including 5 homozygous occurrences. This frequency significantly exceeds the maximal expected allele frequency for a pathogenic variant in NBN (0.25%), suggesting this is a benign polymorphism found primarily in population(s) of African origin. In addition, multiple clinical laboratories have classified this variant as benign/likely benign. One internal sample with this variant also carried a deleterious variant PMS2 c.2186_2187delTC, supporting bening outcome. Taken together, this variant has been classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000121615	SCV000806429	benign	not specified	2017-09-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589914	SCV001473077	benign	not provided	2023-01-06	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225384	SCV002505274	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498572	SCV002808348	likely benign	Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia	2022-05-25	criteria provided, single submitter	clinical testing
ITMI	RCV000121615	SCV000085813	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000128986	SCV000788075	likely benign	Hereditary cancer-predisposing syndrome	2017-09-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000121615	SCV001548835	benign	not specified		no assertion criteria provided	clinical testing	The NBN p.Asn716Asp variant was identified in 1 of 164 proband chromosomes (frequency: 0.006) from individuals or families with cancer and was present in 5 of 1362 control chromosomes (frequency: 0.004) from healthy individuals (Wang 2013, Bodian 2014). The variant was also identified in the following databases: dbSNP (ID: rs72563785) as "With other allele", ClinVar (5x benign, 1x uncertain significance), Clinvitae, and Zhejiang Colon Cancer Database. The variant was not identified in the Cosmic or LOVD 3.0 databases. The variant was identified in control databases in 716 of 277088 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 651 of 24032 chromosomes (freq: 0.03). The p.Asn716 residue is conserved in mammals but not in more distantly related organisms. However four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Natera, Inc.	RCV000168432	SCV002078506	likely benign	Microcephaly, normal intelligence and immunodeficiency	2019-10-31	no assertion criteria provided	clinical testing