Submissions for variant NM_002485.5(NBN):c.1222A>G (p.Lys408Glu)

gnomAD frequency: 0.00276  dbSNP: rs34120922

Total submissions: 16

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	2024-01-29	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	This alteration is classified as likely 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.
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
Eurofins Ntd Llc (ga)	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	2023-08-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588672	SCV000889543	benign	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000200989	SCV002071522	benign	not specified	2018-07-30	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225329	SCV002505292	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115778	SCV002536578	benign	Hereditary cancer-predisposing syndrome	2020-09-29	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002490777	SCV002796106	likely benign	Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia	2021-11-21	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315641	SCV004016052	benign	Acute lymphoid leukemia	2023-07-07	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
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000200989	SCV001973164	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000119194	SCV002078589	likely benign	Microcephaly, normal intelligence and immunodeficiency	2019-11-09	no assertion criteria provided	clinical testing