ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1370A>G (p.Asn457Ser) (rs876659312)

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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 RCV000222178 SCV000275638 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000479010 SCV000566294 uncertain significance not specified 2017-04-22 criteria provided, single submitter clinical testing This variant is denoted NBN c.1370A>G at the cDNA level, p.Asn457Ser (N457S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NBN Asn457Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. NBN Asn457Ser occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether NBN Asn457Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000222178 SCV000685711 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590244 SCV000697944 uncertain significance not provided 2016-07-01 criteria provided, single submitter clinical testing Variant summary: The NBN c.1370A>G (p.Asn457Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant, and Asn457 is not located in a known functional domain of the Nibrin protein. This variant was absent in 121360 control chromosomes and has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. In addition, one clinical diagnostic laboratory classified this variant as a VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000636705 SCV000758145 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 457 of the NBN protein (p.Asn457Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 231710). 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 and their clinical significance is uncertain. 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.

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