Submissions for variant NM_002485.5(NBN):c.37+10G>C

gnomAD frequency: 0.00011  dbSNP: rs369408590

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198382	SCV000253388	likely benign	Microcephaly, normal intelligence and immunodeficiency	2024-01-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000198382	SCV000475303	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000432416	SCV000517289	benign	not specified	2015-07-16	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.
Counsyl	RCV000198382	SCV000788803	likely benign	Microcephaly, normal intelligence and immunodeficiency	2017-01-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000859143	SCV001134509	likely benign	not provided	2023-09-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000432416	SCV001821256	likely benign	not specified	2024-04-16	criteria provided, single submitter	clinical testing	Variant summary: NBN c.37+10G>C alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation 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 9.8e-05 in 245690 control chromosomes, predominantly at a frequency of 6.4e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.37+10G>C in individuals affected with Nijmegen Breakage Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 215822). Based on the evidence outlined above, the variant was classified as likely benign.
Genome-Nilou Lab	RCV000198382	SCV002045998	likely benign	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000580931	SCV004014912	likely benign	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000198382	SCV001457056	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-01-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356816	SCV001552082	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The NBN c.37+10G>C variant was not identified in the literature nor was it identified in Cosmic, LOVD 3.0, Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs369408590) as “With other allele”, ClinVar (as uncertain significance by Illumina, likely benign by Invitae, and benign by GeneDx), and Clinvitae (3x) databases. The variant was identified in control databases in 26 of 272116 chromosomes at a frequency of 0.000096 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 23486 chromosomes (freq: 0.000043), European (Non-Finnish) in 9 of 122980 chromosomes (freq: 0.000073), and Ashkenazi Jewish in 16 of 10068 chromosomes (freq: 0.001589), while the variant was not observed in the Other, Latino, East Asian, European Finnish, and South Asian populations. 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 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.