ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1313G>T (p.Ser438Ile) (rs786203131)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166304 SCV000217088 uncertain significance Hereditary cancer-predisposing syndrome 2014-10-22 criteria provided, single submitter clinical testing
Invitae RCV000204846 SCV000259309 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-10-26 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 438 of the NBN protein (p.Ser438Ile). The serine residue is weakly conserved and there is a large physicochemical difference between serine and isoleucine. 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: 186671). 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.
Integrated Genetics/Laboratory Corporation of America RCV000780521 SCV000917849 uncertain significance not specified 2017-09-28 criteria provided, single submitter clinical testing Variant summary: The NBN c.1313G>T (p.Ser438Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide located in the BRCT domain(IPR001357) (InterPro). 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/246062 control chromosomes (gnomAD) at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic NBN variant (0.000125). In addition, multiple clinical diagnostic laboratories in ClinVar have classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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