ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1484C>T (p.Pro495Leu) (rs863224714)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198393 SCV000254765 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 495 of the NBN protein (p.Pro495Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with colorectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 216564). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000223448 SCV000279846 uncertain significance not provided 2016-02-01 criteria provided, single submitter clinical testing This variant is denoted NBN c.1484C>T at the cDNA level, p.Pro495Leu (P495L) at the protein level, and results in the change of a Proline to a Leucine (CCT>CTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NBN Pro495Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. NBN Pro495Leu occurs at a position that is not conserved 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 evidence, it is unclear whether NBN Pro495Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000562638 SCV000662671 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000562638 SCV000906679 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781646 SCV000919857 uncertain significance not specified 2018-12-26 criteria provided, single submitter clinical testing Variant summary: The variant, NBN c.1484C>T (p.Pro495Leu) results in a non-conservative amino acid change in 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 3.2e-05 in 30930 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1484C>T has been reported in the literature in an individual affected with colorectal cancer (Pearlman_2016). However, this report does 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. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertian significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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