ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.2146A>G (p.Asn716Asp) (rs72563785)

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Total submissions: 14
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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: 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 2020-12-02 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 Clinical Services Laboratory,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 2017-02-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000128986 SCV000685756 benign Hereditary cancer-predisposing syndrome 2014-12-09 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,PreventionGenetics RCV000121615 SCV000806429 benign not specified 2017-09-27 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286495 SCV001473077 benign none provided 2020-02-14 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.

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