Submissions for variant NM_002485.5(NBN):c.381T>C (p.Ala127=)

gnomAD frequency: 0.00266  dbSNP: rs61754795

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000988088	SCV000153939	benign	Microcephaly, normal intelligence and immunodeficiency	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000178181	SCV000170645	benign	not specified	2013-10-24	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.
Ambry Genetics	RCV000157764	SCV000212663	likely benign	Hereditary cancer-predisposing syndrome	2014-07-01	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.
Eurofins Ntd Llc (ga)	RCV000178181	SCV000230195	benign	not specified	2015-03-30	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000178181	SCV000539868	likely benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple assertions in clinvar as benign for hereditary cancer predisposing syndrome and microcephaly with normal intelligence and immunodeficiency
Genetic Services Laboratory, University of Chicago	RCV000178181	SCV000595911	benign	not specified	2021-05-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000178181	SCV000806439	benign	not specified	2017-02-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000119323	SCV000888340	benign	not provided	2022-11-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000988088	SCV001137668	likely benign	Microcephaly, normal intelligence and immunodeficiency	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000119323	SCV001155449	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	NBN: BP4, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000119323	SCV001156821	benign	not provided	2023-08-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000988088	SCV001324899	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Sema4, Sema4	RCV000157764	SCV002536676	benign	Hereditary cancer-predisposing syndrome	2020-03-23	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002498545	SCV002807804	benign	Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia	2021-12-23	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315708	SCV004016057	benign	Acute lymphoid leukemia	2023-07-07	criteria provided, single submitter	clinical testing
Harris Lab, University of Minnesota	RCV000119323	SCV000154182	not provided	not provided		no assertion provided	not provided
True Health Diagnostics	RCV000157764	SCV000788080	likely benign	Hereditary cancer-predisposing syndrome	2017-09-21	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000119323	SCV001550870	likely benign	not provided		no assertion criteria provided	clinical testing	The NBN p.Ala127Ala variant was identified in 1 of 194 proband chromosomes (frequency: 0.005) from French Canadian individuals or families non BRCA1/2 breast cancer and was not identified in 144 control chromosomes from healthy individuals (Desjardins 2009). The variant was also identified in dbSNP (ID: rs61754795) “With other allele”, ClinVar (classified benign by GeneDx, EGL Genetic Diagnostics (Eurofins Clinical Diagnsotics), Color Genomics Inc, Invitae; likely benign by Ambry Genetics and Lab for Molecular Medicine (Partners HealthCare Personalized Medicine); and classification not provided by Harris Lab (U of Minnesota)), Clinvitae (4x), and was not identified in Cosmic, LOVD 3.0, Zhejiang Colon Cancer Database. The variant was identified in control databases in 858 (4 homozygous) of 276910 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 26 of 24026 chromosomes (frequency: 0.001), Other in 16 of 6456 chromosomes (frequency: 0.002), Latino in 54 of 34414 chromosomes (frequency: 0.002), European Non-Finnish in 499 of 126588 chromosomes (frequency: 0.004), European Finnish in 20 of 25630 chromosomes (frequency: 0.0008), Ashkenazi Jewish in 4 of 10150 chromosomes (frequency: 0.0004), and South Asian in 239 (4 homozygotes) of 30782 chromosomes (frequency: 0.008). The p.Ala127= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000157764	SCV001977048	likely benign	Hereditary cancer-predisposing syndrome	2021-09-27	no assertion criteria provided	clinical testing