ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.758C>T (p.Thr253Ile) (rs61754967)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656925 SCV000149714 likely benign not provided 2020-10-22 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24728327, 31278556)
Ambry Genetics RCV000115805 SCV000186084 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-26 criteria provided, single submitter clinical testing The p.T253I variant (also known as c.758C>T), located in coding exon 7 of the NBN gene, results from a C to T substitution at nucleotide position 758. The threonine at codon 253 is replaced by isoleucine, an amino acid with similar properties. This alteration was detected in a cohort of 681 healthy, ancestrally diverse individuals (Bodian DL et al. PLoS One. 2014 Apr;9:e94554). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000168183 SCV000218846 benign Microcephaly, normal intelligence and immunodeficiency 2020-12-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121624 SCV000601701 likely benign not specified 2017-07-06 criteria provided, single submitter clinical testing
Counsyl RCV000168183 SCV000796629 likely benign Microcephaly, normal intelligence and immunodeficiency 2017-12-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115805 SCV000910701 likely benign Hereditary cancer-predisposing syndrome 2016-11-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121624 SCV000917861 likely benign not specified 2020-10-22 criteria provided, single submitter clinical testing Variant summary: NBN c.758C>T (p.Thr253Ile) results in a non-conservative amino acid change located in the Nibrin, second BRCT domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 251260 control chromosomes, predominantly at a frequency of 0.0032 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.3- fold the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome phenotype (0.0025), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.758C>T has been reported in the literature in healthy individuals (e.g. Bodian_2014) and at least one cancer cell line (e.g. Sun_2018). These reports do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as benign/ likely benign (n=4) and uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Nilou-Genome Lab RCV000168183 SCV001737165 likely benign Microcephaly, normal intelligence and immunodeficiency 2021-05-18 criteria provided, single submitter clinical testing
ITMI RCV000121624 SCV000085822 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000656925 SCV001554413 likely benign not provided no assertion criteria provided clinical testing The NBN p.Thr253Ile variant was identified in the literature from healthy individuals in 3 of 1362 control chromosomes (frequency: 0.002) (Bodian 2014). The variant was also identified in the following databases: dbSNP (ID: rs61754967) as "With Uncertain significance allele", ClinVar (2x uncertain significance, 2x likely benign), Clinvitae (2x uncertain significance, 1x likely benign), and the Zhejiang Colon Cancer Database. The variant was not identified in the Cosmic or LOVD 3.0 databases. The variant was identified in control databases in 100 of 276924 chromosomes (1 homozygous) at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 1 of 6454 chromosomes (freq: 0.0002) and South Asian in 99 of 30782 chromosomes (freq: 0.003). The variant was not observed in the African, Latino, European, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Thr253 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, 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.

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