Submissions for variant NM_002485.5(NBN):c.797C>T (p.Pro266Leu)

gnomAD frequency: 0.00955  dbSNP: rs769420

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000121625	SCV000170636	benign	not specified	2014-02-05	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	RCV000129165	SCV000183897	benign	Hereditary cancer-predisposing syndrome	2014-12-12	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.
Invitae	RCV001082237	SCV000261615	benign	Microcephaly, normal intelligence and immunodeficiency	2024-02-01	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000425619	SCV000511715	benign	not provided	2016-12-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121625	SCV000806453	benign	not specified	2017-10-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000121625	SCV000889557	benign	not specified	2020-10-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001082237	SCV001321726	benign	Microcephaly, normal intelligence and immunodeficiency	2017-04-28	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000425619	SCV001472667	benign	not provided	2021-07-23	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225386	SCV002505304	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129165	SCV002536718	benign	Hereditary cancer-predisposing syndrome	2020-05-21	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002498573	SCV002811314	likely benign	Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia	2021-10-07	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315763	SCV004016054	benign	Acute lymphoid leukemia	2023-07-07	criteria provided, single submitter	clinical testing
ITMI	RCV000121625	SCV000085823	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000129165	SCV000788082	likely benign	Hereditary cancer-predisposing syndrome	2018-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000121625	SCV001553095	benign	not specified		no assertion criteria provided	clinical testing	The NBN p.Pro266Leu variant was identified in 14 of 2874 proband chromosomes (frequency: 0.005) from individuals or families with various types of cancer and was present in 4 of 1362 control chromosomes (frequency: 0.003) from healthy individuals (Berg 2013, Bodian 2014, Desjardins 2009, Yurgelun 2015). The variant was also identified in the following databases: dbSNP (ID: rs769420) as "With Benign allele", ClinVar (5x benign), Clinvitae (4x benign), and the Zhejiang Colon Cancer Database (1x). The variant was not identified in Cosmic or the LOVD 3.0 database. The variant was identified in control databases in 771 of 276952 chromosomes (11 homozygous) at a frequency of 0.003 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 705 of 24006 chromosomes (freq: 0.03), Other in 5 of 6454 chromosomes (freq: 0.0008), Latino in 44 of 34382 chromosomes (freq: 0.001), European in 4 of 126556 chromosomes (freq: 0.00003), East Asian in 9 of 18864 chromosomes (freq: 0.0005), and South Asian in 4 of 30776 chromosomes (freq: 0.0001). The variant was not observed in the Ashkenazi Jewish or Finnish populations. Various studies utilizing computational algorithms, personal disease history, and family disease history have been performed; most of these studies conclude the variant is not associated with cancer (Berg 2013, Berardinelli 2013, Bodian 2014, Desjardins 2009, Gao 2013, Yurgelun 2015). The p.Pro266 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the leucine variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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.
Natera, Inc.	RCV001082237	SCV002078630	likely benign	Microcephaly, normal intelligence and immunodeficiency	2019-11-12	no assertion criteria provided	clinical testing