Submissions for variant NM_002485.5(NBN):c.1354A>C (p.Thr452Pro)

gnomAD frequency: 0.00075  dbSNP: rs141137543

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131458	SCV000186442	likely benign	Hereditary cancer-predisposing syndrome	2020-04-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000735122	SCV000211450	likely benign	not provided	2020-07-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function This variant is associated with the following publications: (PMID: 30564542, 27443514, 26976419, 25980754, 30309722)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199946	SCV000253386	likely benign	Microcephaly, normal intelligence and immunodeficiency	2025-01-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212747	SCV000595915	uncertain significance	not specified	2017-02-07	criteria provided, single submitter	clinical testing
Mendelics	RCV003492622	SCV000838303	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000735122	SCV000863322	uncertain significance	not provided	2018-09-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212747	SCV000885816	uncertain significance	not specified	2019-04-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212747	SCV000917862	likely benign	not specified	2024-03-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000735122	SCV001134493	likely benign	not provided	2022-01-12	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000199946	SCV002045920	likely benign	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225444	SCV002505291	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131458	SCV002536593	likely benign	Hereditary cancer-predisposing syndrome	2021-08-11	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131458	SCV002819215	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000735122	SCV004224196	uncertain significance	not provided	2022-08-31	criteria provided, single submitter	clinical testing	BP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000735122	SCV001549968	uncertain significance	not provided		no assertion criteria provided	clinical testing	The NBN p.Thr452Pro variant was identified in 2 of 1738 proband chromosomes (frequency: 0.001) from individuals or families with breast or endometrial cancer (Tung 2016, Ring 2016). The variant was also identified with one other NBN variant and a PALB2 variant, in one individual with primary male breast cancer and primary prostate cancer, though its significance was not conclusive (Kolli 2018). The variant was also identified in dbSNP (ID: rs141137543) as "With other allele", in ClinVar (classified as likely benign by GeneDx and Invitae; uncertain significance by Ambry Genetics, University of Chicago, Mendelics, EGL and ARUP Laboratories), LOVD 3.0 (classified as effect unknown by one submitter). The variant was identified in control databases in 72 of 276950 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 61 of 24010 chromosomes (freq: 0.003), Other in 1 of 6456 chromosomes (freq: 0.0002), Latino in 9 of 34394 chromosomes (freq: 0.0003), European Non-Finnish in 1 of 126548 chromosomes (freq: 0.000008); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Thr452 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003905237	SCV004719233	likely benign	NBN-related disorder	2022-12-07	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).