Submissions for variant NM_002485.5(NBN):c.283G>A (p.Asp95Asn)

gnomAD frequency: 0.00188  dbSNP: rs61753720

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000121616	SCV000149701	likely benign	not specified	2018-01-10	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123216	SCV000166521	benign	Microcephaly, normal intelligence and immunodeficiency	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115792	SCV000183950	benign	Hereditary cancer-predisposing syndrome	2014-07-24	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.
Genetic Services Laboratory, University of Chicago	RCV000121616	SCV000248137	benign	not specified	2021-05-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588621	SCV000601688	benign	not provided	2019-08-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588621	SCV000697966	benign	not provided	2016-04-18	criteria provided, single submitter	clinical testing	Variant summary: The variant of interest causes a missense change involving a conserved nucleotide with 3/4 in silico programs (SNPs&GO not captured here due to low reliability index) predict a "deleterious" outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 225/121130 (1/538), which exceeds the predicted maximum expected allele frequency for a pathogenic NBN variant of 1/8000 for HBOC. The variant of interest has been reported in multiple affected individuals (ALL, OvC, BrC) with limited information ie lack of co-occurrence and co-segregation data. In addition, multiple reputable clinical laboratories cite the variant with a classification of "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign.
CeGaT Center for Human Genetics Tuebingen	RCV000588621	SCV000780920	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	NBN: BP1, BS1
PreventionGenetics, part of Exact Sciences	RCV000588621	SCV000806433	likely benign	not provided	2017-06-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000123216	SCV000838316	likely benign	Microcephaly, normal intelligence and immunodeficiency	2018-07-02	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000121616	SCV000856761	likely benign	not specified	2017-09-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588621	SCV000885815	benign	not provided	2023-08-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000123216	SCV001324900	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000123216	SCV001439193	likely benign	Microcephaly, normal intelligence and immunodeficiency	2020-08-19	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000123216	SCV001737210	likely benign	Microcephaly, normal intelligence and immunodeficiency	2021-05-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115792	SCV002536660	likely benign	Hereditary cancer-predisposing syndrome	2021-04-13	criteria provided, single submitter	curation
Mayo Clinic Laboratories, Mayo Clinic	RCV000588621	SCV004224197	uncertain significance	not provided	2022-10-06	criteria provided, single submitter	clinical testing	BS1
ITMI	RCV000121616	SCV000085814	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000115792	SCV000788078	likely benign	Hereditary cancer-predisposing syndrome	2018-02-14	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000121616	SCV001552363	benign	not specified		no assertion criteria provided	clinical testing	The NBN p.Asp95Asn variant was identified in 15 of 7572 proband chromosomes (frequency: 0.002) from individuals with breast, larynx cancer and acute lymphoblastic leukemia and was present in 14 of 8336 control chromosomes (frequency: 0.002) from healthy individuals (Desjardins 2009, Ziolkowska 2007, Varon 2011, Ramus 2015). The variant was identified in dbSNP (rs61753720) as “with uncertain significance, other allele” also identified in ClinVar (interpreted as "likely benign" by GeneDx and 6 others, "benign" by Invitae and 3 others, "uncertain significance" by 2 others) and LOVD 3.0 (observed 4x). The variant was identified in control databases in 477 of 277,154 chromosomes (1 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 18 of 24,028 chromosomes (freq: 0.0007), Other in 7 of 6466 chromosomes (freq: 0.001), Latino in 22 of 34,414 chromosomes (freq: 0.0006), European in 365 of 126,674 chromosomes (freq: 0.003), Ashkenazi Jewish in 40 of 10,150 chromosomes (freq: 0.004), Finnish in 13 of 25,784 chromosomes (freq: 0.0005), and South Asian in 12 of 30,778 chromosomes (freq: 0.0004). The variant was not observed in the East Asian population. In the control population, the variant exceeds the maximum expected allele frequency (0.0001) for a pathogenic NBN variant leading to the likelihood of a benign classification. The p.Asp95 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000588621	SCV001742309	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000588621	SCV001806806	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000121616	SCV001927457	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000123216	SCV002078676	benign	Microcephaly, normal intelligence and immunodeficiency	2020-01-15	no assertion criteria provided	clinical testing