ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1720T>A (p.Leu574Ile) (rs142334798)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587365 SCV000149693 likely benign not provided 2021-09-21 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 15855896, 23555315, 28135145, 27621404, 29458332, 26928227, 14684699, 27978560, 24728327, 26787654, 26315354, 26976419)
Invitae RCV000123208 SCV000166513 benign Microcephaly, normal intelligence and immunodeficiency 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115784 SCV000186608 benign Hereditary cancer-predisposing syndrome 2016-06-22 criteria provided, single submitter clinical testing No disease association in appropriately sized case-control study(ies)
Genetic Services Laboratory, University of Chicago RCV000121614 SCV000595907 likely benign not specified 2018-04-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587365 SCV000601677 benign not provided 2019-06-19 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000121614 SCV000604437 uncertain significance not specified 2017-02-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115784 SCV000690675 likely benign Hereditary cancer-predisposing syndrome 2015-01-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587365 SCV000697951 benign not provided 2016-01-11 criteria provided, single submitter clinical testing
Counsyl RCV000123208 SCV000799373 likely benign Microcephaly, normal intelligence and immunodeficiency 2018-04-16 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000587365 SCV000806417 likely benign not provided 2017-06-09 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000123208 SCV001324787 likely benign Microcephaly, normal intelligence and immunodeficiency 2017-08-14 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000587365 SCV001500511 uncertain significance not provided 2020-07-01 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000123208 SCV001716361 likely benign Microcephaly, normal intelligence and immunodeficiency 2021-05-18 criteria provided, single submitter clinical testing
ITMI RCV000121614 SCV000085812 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354070 SCV001548593 likely benign Malignant tumor of breast no assertion criteria provided clinical testing NBN, EXON11, c.1720T>A, p.Leu574Ile, Heterozygous, Likely Benign The NBN p.Leu574Ile variant was identified in 7 of 8650 proband chromosomes (frequency 0.0008) from individuals or families with breast and/or ovarian cancer or colorectal cancer and was present in 9 of 8838 (frequency 0.001) control chromosomes from healthy individuals (Heikkinen_2003_14684699, Tung_2016_26976419, Pearlman_2016_27978560, Ramus_2015_26315354, Bodian_2014_24728327). The variant was also identified in the following databases: dbSNP (ID: rs142334798) as “With Uncertain significance, other allele”, ClinVar and Clinvitae databases (4x classified as uncertain significance by Invitae, University of Chicago, Quest Diagnostics, ARUP; 2x classified as likely benign by Ambry Genetics and GeneDx; 1x no classification by ITMI), and the Zhejiang Colon Cancer Database (1x classified as probably pathogenic; 1x classified as pathogenicity unknown). The variant was not identified in the COSMIC or LOVD 3.0 databases. The variant was identified in control databases in 192 of 276828 chromosomes (2 homozygous) at a frequency of 0.0007 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Observations by population included African in 1 of 24004 chromosomes (freq: 0.000042), “Other” in 3 of 6456 chromosomes (freq: 0.000465), Latino in 3 of 34414 chromosomes (freq: 0.000087), European Non-Finnish in 130 of 126478 chromosomes (freq: 0.001028), European Finnish in 37 of 25688 chromosomes (freq: 0.00144), and South Asian in 18 of 30778 chromosomes (freq: 0.000585); the variant was not observed in the Ashkenazi Jewish, or East Asian populations. The p.Leu574Ile residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000587365 SCV001800455 likely benign not provided no assertion criteria provided clinical testing

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