ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.283G>A (p.Asp95Asn) (rs61753720)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 21
Download table as spreadsheet
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.
Invitae RCV000123216 SCV000166521 benign Microcephaly, normal intelligence and immunodeficiency 2020-12-01 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: 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 likely benign not specified 2019-07-02 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
Color Health, Inc RCV000115792 SCV000685770 likely benign Hereditary cancer-predisposing syndrome 2015-02-06 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 Praxis fuer Humangenetik Tuebingen RCV000588621 SCV000780920 uncertain significance not provided 2018-07-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics 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
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000121616 SCV000856761 likely benign not specified 2017-09-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282104 SCV000885815 benign none provided 2019-11-26 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000123216 SCV001439193 likely benign Microcephaly, normal intelligence and immunodeficiency 2020-08-19 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000123216 SCV001737210 likely benign Microcephaly, normal intelligence and immunodeficiency 2021-05-18 criteria provided, single submitter clinical testing
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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.