Submissions for variant NM_002485.5(NBN):c.1124+6G>T

gnomAD frequency: 0.00013  dbSNP: rs375862750

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000127086	SCV000170639	benign	not specified	2014-02-05	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.
Invitae	RCV000199990	SCV000254760	likely benign	Microcephaly, normal intelligence and immunodeficiency	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000127086	SCV000697937	uncertain significance	not specified	2019-05-23	criteria provided, single submitter	clinical testing	Variant summary: NBN c.1124+6G>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 251304 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (0.00012 vs 0.0025), allowing no conclusion about variant significance. c.1124+6G>T has been reported in the literature in individuals affected with breast cancer and colorectal cancer (Tung_2014, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. A co-occurrence with a pathogenic variant has been reported (BRCA1 c.4357+1G>A; LabCorp), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two labs classified the variant as likely benign while two classified as VUS. Based on the evidence outlined above, the variant was classified as a VUS - possibly benign variant.
Counsyl	RCV000199990	SCV000798092	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2018-02-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000587851	SCV000806408	likely benign	not provided	2017-11-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587851	SCV001469583	likely benign	not provided	2021-07-20	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000199990	SCV002045938	likely benign	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000581770	SCV002536574	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-04	criteria provided, single submitter	curation
Ambry Genetics	RCV000581770	SCV002746926	likely benign	Hereditary cancer-predisposing syndrome	2014-09-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Natera, Inc.	RCV000199990	SCV001457042	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-01-10	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354937	SCV001549668	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The NBN c.1124+6G>T variant was not identified in the literature nor was it identified in Cosmic, LOVD 3.0, or Zhejiang Colon Cancer Databases. The variant was identified in dbSNP (ID: rs375862750) “With Uncertain significance allele”, ClinVar (classified with conflicting interpretations of pathogenicity; submitters: benign by GeneDx and uncertain significance by Invitae), and Clinvitae (2x). The variant was identified in control databases in 30 of 277024 chromosomes at a frequency of 0.0001 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The c.1124+6G>T variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. 5 of 5 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.