Submissions for variant NM_002485.5(NBN):c.1914+10G>A

gnomAD frequency: 0.00011  dbSNP: rs577706448

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000192466	SCV000170643	benign	not specified	2014-02-25	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.
Genetic Services Laboratory, University of Chicago	RCV000192466	SCV000248135	uncertain significance	not specified	2014-12-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232925	SCV000287459	benign	Microcephaly, normal intelligence and immunodeficiency	2024-01-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000581136	SCV000685742	likely benign	Hereditary cancer-predisposing syndrome	2015-04-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000232925	SCV000794667	likely benign	Microcephaly, normal intelligence and immunodeficiency	2017-10-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679456	SCV000806422	likely benign	not provided	2017-03-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679456	SCV001134503	benign	not provided	2019-03-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000192466	SCV001337976	likely benign	not specified	2020-01-23	criteria provided, single submitter	clinical testing	Variant summary: NBN c.1914+10G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00027 in 220710 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (0.00027 vs 0.0025), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1914+10G>A in individuals affected with Nijmegen Breakage Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Genome-Nilou Lab	RCV000232925	SCV002045896	benign	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000232925	SCV001455018	likely benign	Microcephaly, normal intelligence and immunodeficiency	2019-11-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357262	SCV001552681	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The NBN c.1914+10G>A variant was not identified in the literature. The variant was identified in dbSNP (rs577706448) as “with other allele”, ClinVar (classified as likely benign by Color, Counsyl and Prevention Genetics; as benign by Invitae and GeneDx and as uncertain significance by University of Chicago) and LOVD 3.0 (observed 1x). The variant was identified in control databases in 59 of 220,710 chromosomes (1 homozygous) at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 34 of 27,638 chromosomes (freq: 0.001), Latino in 15 of 32,818 chromosomes (freq: 0.0005), Other in 1 of 5498 chromosomes (freq: 0.0002), African in 1 of 13,392 chromosomes (freq: 0.00008), European in 7 of 94,896 chromosomes (freq: 0.00007) and Finnish in 1 of 20,126 chromosomes (freq: 0.00005), while the variant was not observed in the Ashkenazi Jewish or East Asian populations. The variant occurs at a non-highly conserved nucleotide 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, 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000679456	SCV001932549	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000679456	SCV001964747	likely benign	not provided		no assertion criteria provided	clinical testing