ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1489A>G (p.Thr497Ala) (rs3026268)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001079822 SCV000166511 benign Microcephaly, normal intelligence and immunodeficiency 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000121612 SCV000170640 benign not specified 2014-01-25 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 RCV000128985 SCV000172874 benign Hereditary cancer-predisposing syndrome 2014-11-28 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.
PreventionGenetics,PreventionGenetics RCV000121612 SCV000309098 benign not specified criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000121612 SCV000595908 benign not specified 2018-01-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121612 SCV000601674 likely benign not specified 2017-01-26 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000121612 SCV000604436 benign not specified 2016-07-26 criteria provided, single submitter clinical testing
Color Health, Inc RCV000128985 SCV000685725 benign Hereditary cancer-predisposing syndrome 2015-02-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759168 SCV000888325 benign not provided 2018-02-27 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001079822 SCV001327035 benign Microcephaly, normal intelligence and immunodeficiency 2017-04-28 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
ITMI RCV000121612 SCV000085810 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000128985 SCV000788076 likely benign Hereditary cancer-predisposing syndrome 2017-08-17 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354750 SCV001549441 benign Malignant tumor of breast no assertion criteria provided clinical testing The NBN p.Thr497Ala variant was identified in 6 of 2520 proband chromosomes (frequency: 0.002) from American individuals or families with a history of Lynch syndrome associated cancers and/or polyps (Yurgelun 2015). The variant was also identified in dbSNP (ID: rs3026268) “With other allele”, ClinVar (classified benign by Invitae, GeneDx, Ambry Genetics, Prevention Genetics, ARUP Laboratories and likely benign by Genetic Services Laboratory (University of Chicago) and Quest Diagnostics Nichols Institute San Juan Capistrano), Zhejiang Colon Cancer Database (1X) and in control databases in 622 (10 homozygous) of 276618 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 569 (10 homozygous) of 24014 chromosomes (freq: 0.02), Other in 4 of 6450 chromosomes (freq: 0.0006), Latino in 39 of 34386 chromosomes (freq: 0.001), European Non-Finnish in 7 of 126274 chromosomes (freq: 0.00006), and South Asian in 3 of 30770 chromosomes (freq: 0.0001); while the variant was not observed in the Ashkenazi Jewish, East Asian, and European Finnish populations.. The variant was not identified in Clinvitae, Cosmic, and LOVD 3.0 databases. The p.Thr497 residue is conserved in in mammals but not in more distantly related organisms however 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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