ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.278C>T (p.Ser93Leu)

gnomAD frequency: 0.00004  dbSNP: rs12721593
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131226 SCV000186180 likely benign Hereditary cancer-predisposing syndrome 2019-07-01 criteria provided, single submitter clinical testing Other strong data supporting benign classification;Subpopulation frequency in support of benign classification
GeneDx RCV000586867 SCV000211471 likely benign not provided 2020-12-23 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25980754, 11325820, 14559852, 28135145, 25176580, 19452044, 15279809, 26315354, 31278556, 31159747)
Invitae RCV000168344 SCV000219033 benign Microcephaly, normal intelligence and immunodeficiency 2021-12-17 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000193311 SCV000248136 uncertain significance not specified 2015-01-13 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131226 SCV000685768 likely benign Hereditary cancer-predisposing syndrome 2020-01-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000193311 SCV000697965 likely benign not specified 2021-12-17 criteria provided, single submitter clinical testing Variant summary: NBN c.278C>T (p.Ser93Leu) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 251486 control chromosomes, predominantly at a frequency of 0.0043 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.278C>T has been reported in the literature in individuals affected with cancer (example: Varon_2001, Taylor_2003, Ramus_2015, Yurgelun_2017, Tsaousis_2019, Dorling_2021). These data do not allow any conclusion about variant significance with Nijmegen Breakage Syndrome or increase risk in cancer. Co-occurrence with other pathogenic variants has been reported (BRCA c.7251_7252delCA, p.H2417fs*3), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters have assessed the variant since 2014: five as uncertain significance, three as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000168344 SCV000799694 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-04-29 criteria provided, single submitter clinical testing
GeneKor MSA RCV000131226 SCV000822085 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000168344 SCV001324901 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genome-Nilou Lab RCV000168344 SCV001652739 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2021-05-18 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000131226 SCV002536658 likely benign Hereditary cancer-predisposing syndrome 2021-02-01 criteria provided, single submitter curation
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354986 SCV001549731 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The NBN p.Ser93Leu variant was identified in 1 of 94 proband chromosomes (frequency: 0.01) from German individuals or families with acute lymphocytic leukemia (ALL) and was not identified in 110 control chromosomes from healthy individuals (Varon 2001). The variant was also identified in dbSNP (ID: rs12721593 “With Uncertain significance allele”), ClinVar (1x as likely benign by Invitae and 3x as uncertain significance by Ambry Genetics, GeneDx, and Genetic Services Laboratory at University of Chicago), LOVD 3.0 (1x), and the Zhejiang University Database (3x). The variant was also identified in control databases in 148 of 246182 chromosomes (2 homozygous) at a frequency of 0.0006 (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 1 of 15292 chromosomes (frequency: 0.00007), Latino in 3 of 33576 chromosomes (frequency 0.00009), European Non-Finnish in 11 of 111668 chromosomes (frequency: 0.0001) and South Asian in 133 of 30778 chromosomes (2 homozygous, frequency: 0.004). The variant was not identified in Cosmic. The p.Ser93Leu variant occurs in the known FHA (forkhead associated) domain of nibrin that is probably involved in protein-protein interactions (Di Masi 2008, Digweed 2004). The p.Ser93 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the Leu variant 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, 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.