Submissions for variant NM_002485.5(NBN):c.1754A>G (p.Glu585Gly)

gnomAD frequency: 0.00001  dbSNP: rs763926389

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461649	SCV000553131	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2024-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 585 of the NBN protein (p.Glu585Gly). This variant is present in population databases (rs763926389, gnomAD 0.03%). This missense change has been observed in individual(s) with Nijmegen breakage syndrome (PMID: 36346689). ClinVar contains an entry for this variant (Variation ID: 411789). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000567576	SCV000662669	likely benign	Hereditary cancer-predisposing syndrome	2021-05-20	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.
PreventionGenetics, part of Exact Sciences	RCV000679454	SCV000806418	uncertain significance	not provided	2017-09-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000679454	SCV001818703	uncertain significance	not provided	2023-03-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Dorling et al., 2021); This variant is associated with the following publications: (PMID: 33471991, 24894818)
Genome-Nilou Lab	RCV000461649	SCV002044556	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282161	SCV002570722	uncertain significance	not specified	2022-07-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002475888	SCV002789626	uncertain significance	Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia	2021-07-26	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358087	SCV001553736	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The NBN p.Glu585Gly variant was not identified in the literature nor was it identified in the Cosmic, LOVD 3.0, Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs763926389) as With Uncertain significance allele, and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 13 of 245824 chromosomes at a frequency of 0.00005 (Genome Aggregation Consortium Feb 27, 2017). The p.Glu585 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc.	RCV000461649	SCV002078544	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-02-12	no assertion criteria provided	clinical testing