ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656925 SCV000149714 uncertain significance not provided 2018-10-29 criteria provided, single submitter clinical testing This variant is denoted NBN c.758C>T at the cDNA level, p.Thr253Ile (T253I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). NBN Thr253Ile was also identified in 3/50 healthy Central Asian individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. NBN Thr253Ile was observed with an allele frequency of 0.32%(99/30,782) in individuals of south Asian ancestry in large population cohorts (Lek 2016). NBN Thr253Ile is located within the BRCT2 domain (Damiola 2014). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NBN Thr253Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115805 SCV000186084 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000168183 SCV000218846 benign Microcephaly, normal intelligence and immunodeficiency 2019-12-21 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 RCV000115805 SCV000910701 likely benign Hereditary cancer-predisposing syndrome 2016-11-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000121624 SCV000917861 likely benign not specified 2018-07-31 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 0.00037 in 277024 control chromosomes, but was observed almost exclusively within the South Asian subpopulation in the gnomAD database at a frequency of 0.0032, including 1 homozygote. The observed variant frequency within South Asian control individuals is approximately 1.3-fold above the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome phenotype (0.0025), suggesting the variant is a benign polymorphism found primarily in populations of South Asian origin. c.758C>T has been reported in the literature in a healthy individual (Bodian_2014). 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 with conflicting assessments including uncertain significance (2x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.
ITMI RCV000121624 SCV000085822 not provided not specified 2013-09-19 no assertion provided reference population

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