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

Total submissions: 5

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.