Submissions for variant NM_002485.5(NBN):c.1489A>G (p.Thr497Ala)

gnomAD frequency: 0.00711  dbSNP: rs3026268

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001079822	SCV000166511	benign	Microcephaly, normal intelligence and immunodeficiency	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000121612	SCV000170640	benign	not specified	2014-01-25	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.
Ambry Genetics	RCV000128985	SCV000172874	benign	Hereditary cancer-predisposing syndrome	2014-11-28	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.
PreventionGenetics, part of Exact Sciences	RCV000121612	SCV000309098	benign	not specified		criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000121612	SCV000595908	benign	not specified	2018-01-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759168	SCV000604436	benign	not provided	2023-06-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000121612	SCV000888325	benign	not specified	2022-05-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001079822	SCV001327035	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.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225382	SCV002505286	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128985	SCV002536605	benign	Hereditary cancer-predisposing syndrome	2020-11-04	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002498571	SCV002795433	likely benign	Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia	2022-04-19	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315761	SCV004016055	benign	Acute lymphoid leukemia	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000759168	SCV004184738	benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	NBN: BP4, BS1, BS2
ITMI	RCV000121612	SCV000085810	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000128985	SCV000788076	likely benign	Hereditary cancer-predisposing syndrome	2017-08-17	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354750	SCV001549441	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The NBN p.Thr497Ala variant was identified in 6 of 2520 proband chromosomes (frequency: 0.002) from American individuals or families with a history of Lynch syndrome associated cancers and/or polyps (Yurgelun 2015). The variant was also identified in dbSNP (ID: rs3026268) “With other allele”, ClinVar (classified benign by Invitae, GeneDx, Ambry Genetics, Prevention Genetics, ARUP Laboratories and likely benign by Genetic Services Laboratory (University of Chicago) and Quest Diagnostics Nichols Institute San Juan Capistrano), Zhejiang Colon Cancer Database (1X) and in control databases in 622 (10 homozygous) of 276618 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 569 (10 homozygous) of 24014 chromosomes (freq: 0.02), Other in 4 of 6450 chromosomes (freq: 0.0006), Latino in 39 of 34386 chromosomes (freq: 0.001), European Non-Finnish in 7 of 126274 chromosomes (freq: 0.00006), and South Asian in 3 of 30770 chromosomes (freq: 0.0001); while the variant was not observed in the Ashkenazi Jewish, East Asian, and European Finnish populations.. The variant was not identified in Clinvitae, Cosmic, and LOVD 3.0 databases. The p.Thr497 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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 this variant meets our laboratory's criteria to be classified as benign.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000128985	SCV002050311	benign	Hereditary cancer-predisposing syndrome	2021-11-09	no assertion criteria provided	clinical testing