Submissions for variant NM_002485.5(NBN):c.1690G>A (p.Glu564Lys)

gnomAD frequency: 0.00030  dbSNP: rs72550742

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212749	SCV000170641	benign	not specified	2014-02-07	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	RCV000129092	SCV000183802	likely benign	Hereditary cancer-predisposing syndrome	2018-09-27	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205604	SCV000261407	benign	Microcephaly, normal intelligence and immunodeficiency	2025-02-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589500	SCV000697949	benign	not provided	2016-03-21	criteria provided, single submitter	clinical testing	Variant summary: The NBN c.1690G>A variant affects a conserved nucleotide, resulting in amino acid change from Glu to Lys. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). Functional studies have not been carried out to prove or disprove these in silico predictions. The variant of interest was observed in a large, broad control population, ExAC, with an allele frequency of 118/121386 (1/1028), predominantly found in the East Asian cohort, 91/8654 (1/95), which exceeds the predicted maximum expected allele frequency for a pathogenic NBN variant of 1/8000 for HBOC. Therefore, suggesting that the variant of interest is a common polymorphism found in population(s) of East Asian origin. The variant has also been cited in cancer patients of East Asian origin, but without evidence of causality (i.e. co-segregation data). In addition, several clinical laboratories classified this variant as benign/likely benign. Taken together, the variant of interest was classified as Benign.
Counsyl	RCV000205604	SCV000788524	likely benign	Microcephaly, normal intelligence and immunodeficiency	2017-01-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589500	SCV000888326	benign	not provided	2023-06-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589500	SCV001245907	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	NBN: BP4, BS1
Illumina Laboratory Services, Illumina	RCV000205604	SCV001324788	benign	Microcephaly, normal intelligence and immunodeficiency	2017-08-21	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.
Sema4, Sema4	RCV000129092	SCV002536614	benign	Hereditary cancer-predisposing syndrome	2020-06-10	criteria provided, single submitter	curation
Breakthrough Genomics, Breakthrough Genomics	RCV000589500	SCV005221698	likely benign	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000205604	SCV001457038	benign	Microcephaly, normal intelligence and immunodeficiency	2020-04-14	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356803	SCV001552068	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The NBN p.Glu564Lys variant was identified in 14 of 634 proband chromosomes (frequency: 0.022) from individuals or families with breast cancer and NBS (Kim 2015, Wang 2013). The variant was also identified in dbSNP (ID: rs72550742) as With Likely benign allele, ClinVar (classified as benign by GeneDx, Invitae; classified as likely benign by Ambry Genetics), Clinvitae (classified as benign by ClinVar, Invitae; classified as likely benign by ClinVar), Zhejiang Colon Cancer Database (1X), databases. The variant was not identified in Cosmic, LOVD 3.0, databases. The variant was identified in control databases in 218 of 276878 chromosomes at a frequency of 0.000787 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Glu564 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. The variant is located with the Nibrin functional domain increasing the likelihood that it may have clinical significance. 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.
References (PMIDs): 25712764, 24349281