Submissions for variant NM_002485.5(NBN):c.266G>C (p.Arg89Pro)

gnomAD frequency: 0.00014  dbSNP: rs747315554

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164059	SCV000214667	likely benign	Hereditary cancer-predisposing syndrome	2021-11-30	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	RCV000473711	SCV000553055	likely benign	Microcephaly, normal intelligence and immunodeficiency	2024-12-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000483231	SCV000565302	uncertain significance	not provided	2024-05-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a pediatric patient with glioma (PMID: 26580448); This variant is associated with the following publications: (PMID: 24894818, 36346689, 26580448)
Counsyl	RCV000473711	SCV000791223	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2017-05-04	criteria provided, single submitter	clinical testing
Mendelics	RCV000473711	SCV000838317	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2018-07-02	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000473711	SCV002045247	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164059	SCV002536656	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-25	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354099	SCV001548629	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The NBN p.Arg89Pro variant was identified in 1 of 2240 proband chromosomes (frequency: 0.0005) from individuals or families with Low Grade Glioma (Zhang 2015). The variant was also identified in dbSNP (ID: rs747315554) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, GeneDx, Color Genomics, Counsyl). The variant was not identified in Cosmic, LOVD 3.0, or Zhejiang University Databases. The variant was identified in control databases in 19 of 246202 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 10 of 33582 chromosomes (freq: 0.0003), European in 9 of 111678 chromosomes (freq: 0.00008), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Arg89 residue is not 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.	RCV000473711	SCV002078677	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-07-10	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745239	SCV005342651	uncertain significance	NBN-related disorder	2024-07-08	no assertion criteria provided	clinical testing	The NBN c.266G>C variant is predicted to result in the amino acid substitution p.Arg89Pro. This variant has been reported in an individual with low grade glioma (Zhang et al. et al 2015. PubMed ID: 26580448, Table S4b). This variant is reported in 0.028% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations in ClinVar from a variant of uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/184749/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.