ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.506G>A (p.Arg169His) (rs776134250)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166315 SCV000217100 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000214523 SCV000279532 uncertain significance not provided 2019-01-18 criteria provided, single submitter clinical testing This variant is denoted NBN c.506G>A at the cDNA level, p.Arg169His (R169H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). Waltes et al. (2009) reported this variant in an individual with symptoms overlapping with Nijmegen Breakage syndrome; however, this individual also carried compound heterozygous truncating variants in the RAD50 gene, to which the authors attributed the patient's phenotype. NBN Arg169His was not observed at a significant allele frequency in large population cohorts (Lek 2016). NBN Arg169His is located within the BRCT1 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 Arg169His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000460960 SCV000553079 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 169 of the NBN protein (p.Arg169His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs776134250, ExAC 0.01%). This variant has been observed in an individual with Nijmegen breakage syndrome (PMID: 19409520). However, in that individual pathogenic alleles were also identified in the RAD50 gene, which suggests that this c.506G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 186682). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000166315 SCV000685793 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780528 SCV000917860 uncertain significance not specified 2018-07-31 criteria provided, single submitter clinical testing Variant summary: NBN c.506G>A (p.Arg169His) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 277042 control chromosomes. This frequency is not higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (3.6e-05 vs 0.0025), allowing no conclusion about variant significance. c.506G>A has been reported in the literature in individual with clinical features suggestive of Nijmegen Breakage Syndrome; however, clinical presentation in the patient was likely due to presence of bi-allelic mutations in the RAD50 gene (c.3277C>T/c.3939A>T, p.R1093X/p.X1313YextX*66; Waltes_2009). This report does not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. In addition, this variant was identified in 2 breast cancer patients of German and Polish ancestry without strong evidence for causality (unpublish data). 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 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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