ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1222A>G (p.Lys408Glu) (rs34120922)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588672 SCV000149687 likely benign not provided 2020-10-08 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 21346221, 17894553, 26315354, 27978560, 26787654, 28528518, 26898890, 23830515, 28135145, 25117502, 31278556)
Invitae RCV000119194 SCV000153931 benign Microcephaly, normal intelligence and immunodeficiency 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115778 SCV000186613 likely benign Hereditary cancer-predisposing syndrome 2018-09-25 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Color Health, Inc RCV000115778 SCV000537498 likely benign Hereditary cancer-predisposing syndrome 2014-12-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000200989 SCV000697940 benign not specified 2021-05-24 criteria provided, single submitter clinical testing Variant summary: NBN c.1222A>G (p.Lys408Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0007 in 258508 control chromosomes, predominantly at a frequency of 0.0095 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1222A>G has been reported in the literature in individuals affected with larynx cancer, breast cancer, ovarian cancer, and colorectal cancer, without strong evidence for causality (examples- Ziolkowska_2007, Ramus_2015, Tung_2015, Caminsky_2016, Pearlman_2016, Young_2016, Cock-Rada_2017, Yurgelun_2017, Bishop_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. At-least one co-occurrence with another pathogenic variant has been reported (BRCA2 c.9253dupA, p.Thr3085Asnfs*26, Tung_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=2)/likely benign (n=5). Based on the evidence outlined above, the variant was classified as benign.
Counsyl RCV000119194 SCV000799488 likely benign Microcephaly, normal intelligence and immunodeficiency 2018-04-19 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000200989 SCV000859935 likely benign not specified 2018-03-13 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000588672 SCV000885819 likely benign not provided 2017-08-15 criteria provided, single submitter clinical testing This variant has not been reported in association with primary immunodeficiency in medical literature or in gene specific variation databases. This variant is listed in the genome Aggregation Database (gnomAD) with an African population frequency of 0.9 percent (identified on 221 out of 24,028 chromosomes). The lysine at position 408 is weakly conserved (Alamut v.2.9.0) and computational analyses of the effects of the p.Lys408Glu variant on protein structure and function indicate a neutral effect (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Based on these observations, the p.Lys408Glu variant is likely to be benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588672 SCV000889543 benign not provided 2019-05-08 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000588672 SCV001809640 likely benign not provided no assertion criteria provided clinical testing

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