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

gnomAD frequency: 0.00767  dbSNP: rs116735828

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129181	SCV000183916	benign	Hereditary cancer-predisposing syndrome	2014-12-02	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000988092	SCV000262314	benign	Microcephaly, normal intelligence and immunodeficiency	2024-02-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000389618	SCV000332541	benign	not specified	2015-06-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000389618	SCV000806437	benign	not specified	2017-01-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759176	SCV000888338	benign	not provided	2022-09-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000988092	SCV001137672	benign	Microcephaly, normal intelligence and immunodeficiency	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759176	SCV001157388	benign	not provided	2020-04-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000988092	SCV001327165	benign	Microcephaly, normal intelligence and immunodeficiency	2017-05-01	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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
GeneDx	RCV000759176	SCV001865616	benign	not provided	2018-11-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30306255, 25980754, 25318351, 24549055)
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225425	SCV002505322	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129181	SCV002536670	benign	Hereditary cancer-predisposing syndrome	2020-01-30	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000759176	SCV003917616	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	NBN: BP4, BS1, BS2
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315872	SCV004016048	benign	Acute lymphoid leukemia	2023-07-07	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000129181	SCV000788079	likely benign	Hereditary cancer-predisposing syndrome	2018-01-05	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000988092	SCV001457059	benign	Microcephaly, normal intelligence and immunodeficiency	2020-06-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354386	SCV001548992	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The NBN c.37+5G>A variant was identified in 4 of 1626 proband chromosomes (frequency: 0.002) from individuals or families with breast and ovarian cancer (Castera 2014, Yorczyk 2015). The variant was also identified in dbSNP (ID: rs116735828) as With Benign allele, ClinVar (classified as benign by Ambry Genetics, Invitae), Clinvitae (classified as benign by ClinVar, Invitae), LOVD 3.0, databases. The variant was identified in control databases in 755(12 homozygous) of 272168 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 549 of 23426 chromosomes (freq: 0.023). The c.37+5G>A variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% 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.